REVERSAL BINDING AGENTS FOR ANTI-FACTOR XI/XIa ANTIBODIES AND USES THEREOF

ABSTRACT

The present disclosure relates to reversal agents, which specifically bind to anti-Factor XI and/or anti-Factor XIa antibodies, and reverse one or more anticoagulant effects of the anti-Factor XI and/or anti-Factor XIa antibodies, as well as to methods of use thereof, such as methods for reversing anticoagulant effects of such anti-Factor XI and/or anti-Factor XIa antibodies, and to related methods for managing bleeding or bleeding risks.

This application claims the benefit of U.S. Provisional Application No.62/341,574 filed on May 25, 2016 and U.S. Provisional Application No.62/438,754 filed on Dec. 23, 2016, each of which is hereby incorporatedby reference in its entirety.

The instant application contains a Sequence Listing which has beensubmitted electronically in ASCII format and is hereby incorporated byreference in its entirety. Said ASCII copy, created on May 22, 2017, isnamed “PAT057330-WO-PCT_SL.txt” and is 238,587 bytes in size. Throughoutthe text of this application, should there be a discrepancy between thetext of the specification (e.g., Tables 1 and 2) and the sequencelisting, the text of the specification shall prevail.

TECHNICAL FIELD

The present disclosure relates to binding agents (e.g., anti-idiotypeantibodies), which specifically binds to anti-Factor XI and/oranti-Factor XIa (“anti-FXI/FXIa”) antibodies, and reverses one or moreanticoagulant effects of the anti-Factor XI and/or anti-Factor XIaantibodies, as well as to methods of use thereof, such as methods forreversing anticoagulant effects of such anti-Factor XI and/oranti-Factor XIa antibodies.

BACKGROUND

Thrombosis refers to thrombus formation inside blood vessels, subsequentto a combination of hereditary and acquired risk factors, known asthrombophilia or hypercoagulable states. Vessel wall damage, stasis,increased platelets reactivity and activation of clotting factors aresome of the fundamental features of thrombosis. Thrombosis can occur inboth venous and arterial circulation and can result in the developmentof deep vein thrombosis (DVT), pulmonary embolism, and stroke. If athrombus occurs in the arterial system, down-stream ischemia can occur,leading to acute coronary syndromes (ACS), ischemic stroke, and acutelimb ischemia. Thrombus formation in the venous system typically leadsto deep venous thrombosis, pulmonary embolism and chronic thromboembolicpulmonary hypertension. Clots may also form in the left atrial appendagein patients with atrial fibrillation (AF), and dislodged thrombi mayresult in potentially devastating complications, i.e. thromboembolicstroke and systemic embolism. The currently available antithromboticmedications, including low molecular weight heparin (LMWH), thrombininhibitors, and Factor Xa (FXa) inhibitors, are all associated with asignificant risk of bleeding (Weitz J. I. (2010) Thromb. Haemost. 103,62). The development of an antithrombotic agent that does not affecthemostasis, and therefore does not result in bleeding complications, aswell as specific reversal agents, would be highly desirable.

Current anticoagulants are either injected or taken orally. Theinjectable anticoagulant LMWH is widely used and offers an improvedtherapeutic profile over formerly applied unfractionated heparin. Forthe past few decades the most commonly used oral anticoagulant has beenwarfarin. Warfarin has a narrow therapeutic window that requiresfrequent monitoring of the coagulation status, and shows a variety ofdrug-drug interactions. More recently, orally available direct FXa andthrombin inhibitors entered the anticoagulant market and areincreasingly applied.

LMWHs, FXa inhibitors, and thrombin inhibitors are all efficacious inthe prevention of post-operative venous thromboembolic disease, in thetreatment of spontaneous DVT and pulmonary embolism, and in the strokeprevention in atrial fibrillation. However, these anticoagulants arealso associated with bleeding complications that were generallycomparable to those observed with the older drugs warfarin andunfractionated heparin. In the ADVANCE-2 clinical trial, the FXainhibitor apixaban (Eliquis) was compared to the LMWH enoxaparin inpatients after total knee replacement. While acute apixaban therapy wasmore effective at preventing venous thromboembolic disease thanenoxaparin, both agents were associated with a significant risk ofbleeding. Clinically relevant bleeding occurred in 4% of patientsreceiving apixaban and in 5% of patients treated with enoxaparin(Lassen, M. R., et al. (2009) N. Engl. J. Med. 361, 594).

In the RE-LY trial, the direct thrombin inhibitor dabigatran (Pradaxa)was compared to warfarin in patients with atrial fibrillation and a riskof stroke (Connolly, S. J., et al. (2009) N. Engl. J. Med. 361, 1139).Chronic dabigatran therapy was associated with a significantly lowerrisk of stroke or systemic embolism. However, major bleedingcomplications occurred in 3.1% of patients receiving 150 mg per day ofdabigatran and in 3.4% of patients receiving warfarin (p=0.31).

Atrial fibrillation (AF) remains the most common cardiac arrhythmia inclinical practice, accounting for approximately one third ofhospitalizations for cardiac dysrhythmias. Currently, it is estimated toaffect more than 6 million patients in Europe and approximately 2.3million in the United States, and this number continues to grow rapidlybecause of the increasing proportion of the aging population. It isestimated that approximately 5% of the population over the age of 65years, and 10% of people aged over 80 years, will develop AF, however,the prevalence of AF is increasing beyond what is explained by agealone. AF risk factors such as hypertension, congestive heart failure,left ventricular hypertrophy, coronary artery disease and diabetesmellitus, and obstructive sleep apnea are also on the rise. As such, thenumber of affected individuals with AF is expected to increase two tothree times over the next three decades in western populations. (Kanneland Benjamin (2008) Med Clin North Am. 2008; 92:17-40; Bunch, et al.(2012) J Innovations of Card Rhythm Manag 2012; 3: 855-63).

The principal risk of AF is a four- to five fold increase in embolicstroke. The attributable risk for stroke associated with AF increasessteeply with age to 23.5% at ages 80 to 89. AF is associated with adoubling of mortality in both genders (Kannel and Benjamin 2008). AF isalso independently associated with cognitive decline and all forms ofdementia (Marzona, et al. (2012) CMAJ 2012; 184: 329-36; Geita et al2013; Bunch et al 2012).

Most patients with AF require life-long anticoagulation therapy toprevent cardioembolic stroke and systemic embolism. The CHA2DS2-VAScrisk score is a validated and widely used stratification tool to predictthromboembolic risk in atrial fibrillation patients and to identifypatients who should benefit from anticoagulation therapy (LIP 2011;Camm, et al. (2012) Eur Heart J 2012; 33: 2719-2747); the accumulatedevidence shows that CHA2DS2-VASc is at least as accurate as or possiblybetter than, scores such as CHADS2 in identifying patients who developstroke and thromboembolism and definitively better at identifying ‘trulylow-risk’ patients with AF. It is estimated that 85 to 90% of AFpatients will require anticoagulation therapy.

In a meta-analysis comprising 6 trials which evaluated the effect ofvitamin K antagonists (VKA) in reducing stroke and systemic embolism, ahighly significant risk reduction in stroke incidence (relative riskreduction of 67% for stoke) was observed. All-cause mortality wassignificantly reduced (26%) by adjusted-dose VKA vs. control (Hart,Pearce, and Aguilar (2007) Ann Intern Med 2007; 146:857-867). Aninternational normalized ratio (INR) target between 2 and 3 wasassociated with best benefit-risk ratio (Hylek et al (2003) N Engl JMed; 349:1019-1026) and universally adopted by international andnational guidelines.

In recent years, new oral anticoagulants (NOAC) also referred to asdirect oral anticoagulants (DOAC) have been approved and introduced toclinical practice. These drugs are at least as effective or even betterthan warfarin for reducing thrombo-embolic disease (Connolly, et al.(2009) N Engl J Med; 361:1139-51; Connolly, et al. (2011) N Engl J Med;364:806-17; Patel, et al. (2011) N Engl J Med 2011; 365:883-91). NOACwere also associated with large reductions in the most devastatingcomplications of warfarin namely hemorrhagic stroke and intracranialhemorrhage. Major bleeding events were similar or slightly lower thanwell conducted warfarin therapy. In addition NOAC are associated with alower potential for drug-drug interaction than warfarin and could beused without routine monitoring; this is expected to ease their use ineveryday medical practice.

Despite recent improvements, bleeding risk continues to be high with theuse of anticoagulants. For instance, the annual incidence of major andclinically relevant non major bleeding was 14.9% and the annualincidence of major bleeding events was 3.6% in patients treated withrivaroxaban in the ROCKET study (Patel et al 2011). The annual incidenceof major bleeding was >5% in patients at a high risk for bleedingdefined as HAS Bled risk score ≥3 (Gallego, et al. (2012) Carc ArrhythmElectrophysiol.; 5:312-318). Major bleeding is a particularly relevantclinical outcome; for instance in the ROCKET study, once major bleedinghas occurred, all-cause mortality rate was 20.4% in the rivaroxabangroup and 26.1% in the warfarin group. Once major bleeding events haveoccurred stroke and systemic embolism occurred in 4.7% and 5.4% ofpatients in rivaroxaban and warfarin groups, respectively (Piccini, etal. (2014) Eur Heart J; 35:1873-80). Hospital stay, transfusion of bloodproducts and resources utilization were also severely impacted by theoccurrence of major bleeding. Bleeding risk is also a major reason fornot receiving anticoagulants in eligible patients. In the Euro HeartSurvey on Atrial Fibrillation comprising data from 182 hospitals in 35countries and 5333 ambulant and hospitalized AF patients, only 67% ofeligible patients received oral anticoagulant at discharge (Nieuwlaat,et al (2005) Eur Heart J;26, 2422-2434). A high unmet medical needtherefore exists for a safer therapy which can reduce AF thromboemboliccomplications such as stroke, systemic embolism, cognitive decline andmortality with comparable efficacy as existing therapy but with a lowerbleeding liability.

Factor XI (FXI) holds important roles in both intrinsic and extrinsiccoagulation pathways and in bridging the initiation and amplificationphases of plasmatic hemostasis (Gailani and Renné (2007) ArteriosclerThromb Vasc Biol; 27(12):2507-13). Both Factor XII and thrombin canactivate FXI, resulting in a sustained thrombin generation andfibrinolysis inhibition. FXI plays a minor role in normal hemostasis ina high tissue factor environment “after vessel injury” whereas itappears to play a key role in thrombosis. Severe FXI deficiency isassociated with a lower incidence of ischemic stroke and venousthromboembolic events (Salomon et al (2008) Blood; 111(8):4113-7;Salomon et al (2011) Thromb Haemost; 105(2):269-73). Furthermore, in apopulation-based study, a survival advantage of severe FXI deficiencywas evoked as a result of a lower incidence of thromboembolic events(Duga and Salomon, (2013) Semin Thromb Hemost; 39(6):621-31). Bleedingmanifestations in subjects with severe FXI deficiency are infrequent,usually mild, injury-related, and affect preferably tissues withincreased fibrinolytic activity such as the oral mucosa, nasal mucosaand urinary tract (Bolton-Maggs, (2000) Haemophilia; 6 Suppl 1:100-9).Bleeding in vital organs is extremely rare or not existing.

Accordingly, as part of efforts to lower bleeding liability, there isalso a high unmet medical need for specific, reversal agents foranticoagulant therapies, for example, in circumstances when reversal ofthe anticoagulant effects of a therapy is needed for emergencysurgery/urgent procedures and in life-threatening or uncontrolledbleeding.

SUMMARY

Lower bleeding risk is associated with anticoagulant therapies involvinganti-FXI/FXIa antibodies, compared to NOACs. For example, anti-FactorXI/FXIa antibody NOV1401 is a human antibody binding to the catalyticdomain of FXI. NOV1401 inhibits both the zymogen (FXI) and the activatedfactor XI (FXIa) with high potency. Anti-FXI/FXIa antibody NOV1401dose-dependently prolonged activated partial thromboplastin time (aPTT)in in vitro and in in vivo studies. After a single subcutaneous (s.c.)administration of NOV1401 at a 3 mg/kg dose, a sustained anticoagulantactivity lasting more than one month was observed in cynomolgus monkeys.Moreover, Anti-FXI/FXIa antibody NOV1401 prevented experimental carotidartery thrombosis induced by FeCl3 and induced prolongation in aPTT inFXI−/− mice reconstituted with human FXI. NOV1401 was well tolerated inthe 13 week Good Laboratory Practice (GLP)-compliant toxicity studyconducted in cynomolgus monkeys.

Despite the lower bleeding risk with anti-FXI/FXIa antibodies, such asantibody NOV1401, compared to NOACs, bleeding events may still happendue to trauma, surgery, procedures, co-medication and high prevalence ofcomorbidities that increase bleeding risk such as hypertension, heartfailure, renal impairment, hepatic impairment, older age, prior bleedingevents, risk of falls, use of antiplatelet agents or non-steroidalanti-inflammatory drugs, etc.

Accordingly, as part of efforts to lower bleeding liability, the presentdisclosure describes strategies to address the high unmet medical needfor specific, reversal agents for anticoagulant therapies, such asanti-Factor XI/XIa antibodies (e.g., anti-FXI/FXIa antibodies whichspecifically bind to the catalytic domain of FXI/FXIa). In specificaspects, managing bleeding or bleeding risk is beneficial incircumstances when reversal of the anticoagulant effects of a therapy isneeded, for example, for emergency surgery/urgent procedures and incases of life-threatening or uncontrolled bleeding. In specific aspects,managing bleeding or bleeding risk is beneficial in patients identifiedas having high bleeding risk (e.g., previous history of bleeding).

The present disclosure relates to binding agents (e.g., anti-idiotypeantibodies and fragments thereof such as Fabs) which specifically bindsto antibodies that specifically bind coagulation Factor XI and XIa(activated Factor XI) (hereinafter, sometimes referred to as “FXI”,“FXIa,” and similar terms), and which are capable of reversing one ormore anticoagulant effects of such anti-FXI/FXIa antibodies (e.g.,capable of reducing aPTT or bleeding time) and/or inhibits binding ofthe antibodies to FXI/FXIa. The present disclosure also relates topharmaceutical compositions comprising the binding agents, and methodsof reversing one or more anticoagulant effects of an anti-FXI/FXIaantibody in a patient (e.g., human patient) being treated with theanti-FXI/FXIa antibody, comprising administering the binding agent. Suchbinding agents capable of reversing one or more anticoagulant effects ofanti-FXI/FXIa antibodies achieve an unmet need in circumstances whenreversal of the anticoagulant effects of a therapy, such as anti-FXI/XIaantibodies, is needed for emergency surgery/urgent procedures and inlife-threatening or uncontrolled bleeding.

In specific aspects, such patients (e.g., human patients) are beingtreated with an anti-FXI/FXIa antibody for the prevention and/ortreatment of thrombosis or thromboembolic disease/disorder (e.g.,thrombic stroke, atrial fibrillation, stroke prevention in atrialfibrillation (SPAF), deep vein thrombosis, venous thromboembolism,pulmonary embolism, acute coronary syndromes (ACS), ischemic stroke,acute limb ischemia, chronic thromboembolic pulmonary hypertension,systemic embolism). In specific aspects, binding agents provided hereinthat reverses one or more anticoagulant effects of anti-FXI/FXIaantibodies are anti-idiotype antibodies, and in further specificaspects, such anti-idiotype antibodies are Fabs. In further specificaspects, such anti-idiotype antibodies are monoclonal antibodies, suchas human monoclonal antibodies, e.g., recombinant human monoclonalantibodies.

In particular aspects, the present disclosure also relates to isolatedpolynucleotides and nucleic acids comprising a sequence encoding abinding agent provided herein, to vectors comprising one or more of thepolynucleotides or nucleic acids provided herein, to host cellscomprising such vectors or polynucleotides or nucleic acids. In specificaspects, the host cells are non-human mammalian cells, such as Chinesehamster ovary (CHO) cells.

Non-limiting embodiments of the present disclosure are described in thefollowing aspects:

1. A binding agent (e.g., human anti-idiotype antibody such as a humananti-idiotype Fab) which specifically binds a target antibody that bindshuman Factor XI (“FXI”) and/or Factor XIa (“FXIa”) within the catalyticdomain, wherein the binding agent inhibits an anticoagulant activity ofthe target antibody, wherein the binding agent binds to the targetantibody with a dissociation constant (K_(D)) of 1 nM or less, andwherein the binding agent is capable of inhibiting the ability of thetarget antibody to delay activated partial thromboplastin time (aPTT) byat least 35%.

2. The binding agent of aspect 1, wherein the target antibody comprises(i) a heavy chain variable region (VH) comprising the amino acidsequence of SEQ ID NO: 12 and a light chain variable region (VL)comprising the amino acid sequence of SEQ ID NO: 23; or (ii) a heavychain comprising the amino acid sequence of SEQ ID NO: 14 and a lightchain comprising the amino acid sequence of SEQ ID NO: 25.

3. The binding agent of aspect 1, wherein the target antibody comprises(i) a VH comprising complementarity determining regions HCDR1, HCDR2 andHCDR3 of a VH comprising the amino acid sequence of SEQ ID NO: 12 and(ii) a VL comprising complementarity determining regions LCDR1, LCDR2,and LCDR3 of a VL comprising the amino acid sequence of SEQ ID NO: 23.

4. The binding agent of aspect 1, wherein the target antibody comprises:

(A)(i) a VH comprising complementarity determining regions HCDR1, HCDR2and HCDR3 comprising the amino acid sequences of SEQ ID NO: 3, SEQ IDNO: 4, and SEQ ID NO: 5, respectively; and (ii) a VL comprisingcomplementarity determining regions LCDR1, LCDR2, and LCDR3 comprisingthe amino acid sequence of SEQ ID NO: 16, SEQ ID NO: 17, and SEQ ID NO:18, respectively;

(B)(i) a VH comprising complementarity determining regions HCDR1, HCDR2and HCDR3 comprising the amino acid sequences of SEQ ID NO: 6, SEQ IDNO: 4, and SEQ ID NO: 5, respectively; and (ii) a VL comprisingcomplementarity determining regions LCDR1, LCDR2, and LCDR3 comprisingthe amino acid sequence of SEQ ID NO: 16, SEQ ID NO: 17, and SEQ ID NO:18, respectively;

(C)(i) a VH comprising complementarity determining regions HCDR1, HCDR2and HCDR3 comprising the amino acid sequences of SEQ ID NO: 7, SEQ IDNO: 8, and SEQ ID NO: 5, respectively; and (ii) a VL comprisingcomplementarity determining regions LCDR1, LCDR2, and LCDR3 comprisingthe amino acid sequence of SEQ ID NO: 19, SEQ ID NO: 20, and SEQ ID NO:21, respectively; or

(D)(i) a VH comprising complementarity determining regions HCDR1, HCDR2and HCDR3 comprising the amino acid sequences of SEQ ID NO: 9, SEQ IDNO: 10, and SEQ ID NO: 11, respectively; and (ii) a VL comprisingcomplementarity determining regions LCDR1, LCDR2, and LCDR3 comprisingthe amino acid sequence of SEQ ID NO: 22, SEQ ID NO: 20, and SEQ ID NO:18, respectively.

5. The binding agent of aspect 1, wherein the target antibody competeswith an anti-FXI/FXIa antibody comprising a heavy chain comprising theamino acid sequence of SEQ ID NO: 14 and a light chain comprising theamino acid sequence of SEQ ID NO: 25.

6. The binding agent of aspect 1, wherein the target antibody binds thesame epitope as an anti-FXI/FXIa antibody comprising a heavy chaincomprising the amino acid sequence of SEQ ID NO: 14 and a light chaincomprising the amino acid sequence of SEQ ID NO: 25.

7. The binding agent of aspect 6, wherein the target antibody binds oneor more epitopes of human FXI and/or FXIa comprising one, two, three,four, five, six, seven, eight, nine, ten, eleven, twelve, thirteen,fourteen, fifteen or more, or all of, amino acid residues selected from:Pro410, Arg413, Leu415, Cys416, His431, Cys432, Tyr434, Gly435, Glu437,Tyr472, Lys473, Met474, Ala475, Glu476, Tyr521, Arg522, Lys523, Leu524,Arg525, Asp526, Lys527, Arg548, His552, Ser575, Ser594, Trp595, Gly596,Glu597, Arg602, Glu603, and Arg604.

8. A binding agent which specifically binds a target antibody that bindshuman FXI and/or FXIa within the catalytic domain, wherein the bindingagent inhibits an anticoagulant activity of the target antibody,

wherein the target antibody comprises (i) a heavy chain variable region(VH) comprising the amino acid sequence of SEQ ID NO: 12 and a lightchain variable region (VL) comprising the amino acid sequence of SEQ IDNO: 23, or (ii) a heavy chain comprising the amino acid sequence of SEQID NO: 14 and a light chain comprising the amino acid sequence of SEQ IDNO: 25; and

wherein the binding agent is an antibody (e.g., human anti-idiotypeantibody) or antigen-binding fragment thereof (e.g., Fab) comprising (1)a VH comprising complementarity determining regions HCDR1, HCDR2, andHCDR3 selected from those set forth in Table 2, and (2) a VL comprisingcomplementarity determining regions LCDR1, LCDR2, and LCDR3 selectedfrom those set forth in Table 2.

9. The binding agent of aspect 8, wherein

the HCDR1 comprises the amino acid sequence GFTF-X1-SAAVH (SEQ ID NO:347), wherein X1 is any amino acid or is S or Q;

the HCDR2 comprises the amino acid sequence RIKSKA-X4-X5-GTTDYAAPVKG(SEQ ID NO: 357), RIKSK-X3-X4-X5-GTTDYAAPVKG (SEQ ID NO: 358),RIKSK-X3-X4-GGTTDYAAPVKG (SEQ ID NO: 349) or RIKSKA-X4-GGTTDYAAPVKG (SEQID NO: 348), wherein X3 is any amino acid or is T or A, X4 is any aminoacid or is S or D, and X5 is any amino acid or is G or A;

the HCDR3 comprises the amino acid sequence DSPSISSYSIPYFSGMDV (SEQ IDNO: 350);

the LCDR1 comprises the amino acid sequence RASQGIRAWLN (SEQ ID NO: 351)or

RASQ-X6-I-X7-X8-X9-LN (SEQ ID NO: 352), wherein X6 is any amino acid oris S or G, X7 is any amino acid or is R or S, X8 is any amino acid or isA or N, and X9 is any amino acid or is W or Y;

the LCDR2 comprises the amino acid sequence AASSLQS (SEQ ID NO: 353);and

the LCDR3 comprises the amino acid sequence HQYITHPPT (SEQ ID NO: 354)or

HQYI-X10-X11-P-X12-T (SEQ ID NO: 355), wherein X10 is any amino acid oris T or A, X11 is any amino acid or is H or K, and X12 is any amino acidor is P or I.

10. The binding agent of aspect 9, wherein

the HCDR1 comprises the amino acid sequence GFTF-X1-SAAVH (SEQ ID NO:347), wherein X1 is S or Q;

the HCDR2 comprises the amino acid sequence RIKSKA-X4-X5-GTTDYAAPVKG(SEQ ID NO: 357), wherein X4 is S or D and X5 is G or A;

the HCDR3 comprises the amino acid sequence DSPSISSYSIPYFSGIVIDV (SEQ IDNO: 350);

the LCDR1 comprises the amino acid sequence RASQGIRAWLN (SEQ ID NO:351);

the LCDR2 comprises the amino acid sequence AASSLQS (SEQ ID NO: 353);and

the LCDR3 comprises the amino acid sequence HQYITHPPT (SEQ ID NO: 354).

11. The binding agent of aspect 8, wherein

the HCDR1 comprises the amino acid sequence SAAVH (SEQ ID NO: 356);

the HCDR2 comprises the amino acid sequence RIKSKA-X4-X5-GTTDYAAPVKG(SEQ ID NO: 357), RIKSK-X3-X4-X5-GTTDYAAPVKG (SEQ ID NO: 358),RIKSK-X3-X4-GGTTDYAAPVKG (SEQ ID NO: 349) or RIKSKA-X4-GGTTDYAAPVKG (SEQID NO: 348), wherein X3 is any amino acid or is T or A, X4 is any aminoacid or is S or D, and X5 is any amino acid or is G or A;

the LCDR1 comprises the amino acid sequence RASQGIRAWLN (SEQ ID NO: 351)or

RASQ-X6-I-X7-X8-X9-LN (SEQ ID NO: 352), wherein X6 is any amino acid oris S or G, X7 is any amino acid or is R or S, X8 is any amino acid or isA or N, and X9 is any amino acid or is W or Y;

the LCDR2 comprises the amino acid sequence AASSLQS (SEQ ID NO: 353);and

the LCDR3 comprises the amino acid sequence HQYITHPPT (SEQ ID NO: 354)or

HQYI-X10-X11-P-X12-T (SEQ ID NO: 355), wherein X10 is any amino acid oris T or A, X11 is any amino acid or is H or K, and X12 is any amino acidor is P or I.

12. The binding agent of aspect 11, wherein

the HCDR1 comprises the amino acid sequence SAAVH (SEQ ID NO: 356);

the HCDR2 comprises the amino acid sequence RIKSKA-X4-X5-GTTDYAAPVKG(SEQ ID NO: 357), wherein X4 is S or D and X5 is G or A;

the HCDR3 comprises the amino acid sequence DSPSISSYSIPYFSGMDV (SEQ IDNO: 350);

the LCDR1 comprises the amino acid sequence RASQGIRAWLN (SEQ ID NO:351);

the LCDR2 comprises the amino acid sequence AASSLQS (SEQ ID NO: 353);and

the LCDR3 comprises the amino acid sequence HQYITHPPT (SEQ ID NO: 354).

13. The binding agent of aspect 8, wherein

-   -   (i) the HCDR1 comprises the amino acid sequence of SEQ ID NO:        91, the HCDR2 comprises the amino acid sequence of SEQ ID NO:        92, the HCDR3 comprises the amino acid sequence of SEQ ID NO:        93, the LCDR1 comprises the amino acid sequence of SEQ ID NO:        107, the LCDR2 comprises the amino acid sequence of SEQ ID NO:        108, and the LCDR3 comprises the amino acid sequence of SEQ ID        NO: 109;    -   (ii) the HCDR1 comprises the amino acid sequence of SEQ ID NO:        94, the HCDR2 comprises the amino acid sequence of SEQ ID NO:        95, the HCDR3 comprises the amino acid sequence of SEQ ID NO:        96, the LCDR1 comprises the amino acid sequence of SEQ ID NO:        110, the LCDR2 comprises the amino acid sequence of SEQ ID NO:        111, and the LCDR3 comprises the amino acid sequence of SEQ ID        NO: 112;    -   (iii) the HCDR1 comprises the amino acid sequence of SEQ ID NO:        97, the HCDR2 comprises the amino acid sequence of SEQ ID NO:        98, the HCDR3 comprises the amino acid sequence of SEQ ID NO:        99, the LCDR1 comprises the amino acid sequence of SEQ ID NO:        113, the LCDR2 comprises the amino acid sequence of SEQ ID NO:        114, and the LCDR3 comprises the amino acid sequence of SEQ ID        NO: 115; or    -   (iv) the HCDR1 comprises the amino acid sequence of SEQ ID NO:        100, the HCDR2 comprises the amino acid sequence of SEQ ID NO:        101, the HCDR3 comprises the amino acid sequence of SEQ ID NO:        102, the LCDR1 comprises the amino acid sequence of SEQ ID NO:        116, the LCDR2 comprises the amino acid sequence of SEQ ID NO:        117, and the LCDR3 comprises the amino acid sequence of SEQ ID        NO: 118.

14. The binding agent of aspect 8, wherein

-   -   (i) the HCDR1 comprises the amino acid sequence of SEQ ID NO:        27, the HCDR2 comprises the amino acid sequence of SEQ ID NO:        28, the HCDR3 comprises the amino acid sequence of SEQ ID NO:        29, the LCDR1 comprises the amino acid sequence of SEQ ID NO:        43, the LCDR2 comprises the amino acid sequence of SEQ ID NO:        44, and the LCDR3 comprises the amino acid sequence of SEQ ID        NO: 45;    -   (ii) the HCDR1 comprises the amino acid sequence of SEQ ID NO:        30, the HCDR2 comprises the amino acid sequence of SEQ ID NO:        31, the HCDR3 comprises the amino acid sequence of SEQ ID NO:        32, the LCDR1 comprises the amino acid sequence of SEQ ID NO:        46, the LCDR2 comprises the amino acid sequence of SEQ ID NO:        47, and the LCDR3 comprises the amino acid sequence of SEQ ID        NO: 48;    -   (iii) the HCDR1 comprises the amino acid sequence of SEQ ID NO:        33, the HCDR2 comprises the amino acid sequence of SEQ ID NO:        34, the HCDR3 comprises the amino acid sequence of SEQ ID NO:        35, the LCDR1 comprises the amino acid sequence of SEQ ID NO:        49, the LCDR2 comprises the amino acid sequence of SEQ ID NO:        50, and the LCDR3 comprises the amino acid sequence of SEQ ID        NO: 51; or    -   (iv) the HCDR1 comprises the amino acid sequence of SEQ ID NO:        36, the HCDR2 comprises the amino acid sequence of SEQ ID NO:        37, the HCDR3 comprises the amino acid sequence of SEQ ID NO:        38, the LCDR1 comprises the amino acid sequence of SEQ ID NO:        52, the LCDR2 comprises the amino acid sequence of SEQ ID NO:        53, and the LCDR3 comprises the amino acid sequence of SEQ ID        NO: 54.

15. The binding agent of aspect 8, wherein

-   -   (i) the HCDR1 comprises the amino acid sequence of SEQ ID NO:        59, the HCDR2 comprises the amino acid sequence of SEQ ID NO:        60, the HCDR3 comprises the amino acid sequence of SEQ ID NO:        61, the LCDR1 comprises the amino acid sequence of SEQ ID NO:        75, the LCDR2 comprises the amino acid sequence of SEQ ID NO:        76, and the LCDR3 comprises the amino acid sequence of SEQ ID        NO: 77;    -   (ii) the HCDR1 comprises the amino acid sequence of SEQ ID NO:        62, the HCDR2 comprises the amino acid sequence of SEQ ID NO:        63, the HCDR3 comprises the amino acid sequence of SEQ ID NO:        64, the LCDR1 comprises the amino acid sequence of SEQ ID NO:        78, the LCDR2 comprises the amino acid sequence of SEQ ID NO:        79, and the LCDR3 comprises the amino acid sequence of SEQ ID        NO: 80;    -   (iii) the HCDR1 comprises the amino acid sequence of SEQ ID NO:        65, the HCDR2 comprises the amino acid sequence of SEQ ID NO:        66, the HCDR3 comprises the amino acid sequence of SEQ ID NO:        67, the LCDR1 comprises the amino acid sequence of SEQ ID NO:        81, the LCDR2 comprises the amino acid sequence of SEQ ID NO:        82, and the LCDR3 comprises the amino acid sequence of SEQ ID        NO: 83; or    -   (iv) the HCDR1 comprises the amino acid sequence of SEQ ID NO:        68, the HCDR2 comprises the amino acid sequence of SEQ ID NO:        69, the HCDR3 comprises the amino acid sequence of SEQ ID NO:        70, the LCDR1 comprises the amino acid sequence of SEQ ID NO:        84, the LCDR2 comprises the amino acid sequence of SEQ ID NO:        85, and the LCDR3 comprises the amino acid sequence of SEQ ID        NO: 86.

16. The binding agent of aspect 8, wherein

-   -   (i) the HCDR1 comprises the amino acid sequence of SEQ ID NO:        123, the HCDR2 comprises the amino acid sequence of SEQ ID NO:        124, the HCDR3 comprises the amino acid sequence of SEQ ID NO:        125, the LCDR1 comprises the amino acid sequence of SEQ ID NO:        139, the LCDR2 comprises the amino acid sequence of SEQ ID NO:        140, and the LCDR3 comprises the amino acid sequence of SEQ ID        NO: 141;    -   (ii) the HCDR1 comprises the amino acid sequence of SEQ ID NO:        126, the HCDR2 comprises the amino acid sequence of SEQ ID NO:        127, the HCDR3 comprises the amino acid sequence of SEQ ID NO:        128, the LCDR1 comprises the amino acid sequence of SEQ ID NO:        142, the LCDR2 comprises the amino acid sequence of SEQ ID NO:        143, and the LCDR3 comprises the amino acid sequence of SEQ ID        NO: 144;    -   (iii) the HCDR1 comprises the amino acid sequence of SEQ ID NO:        129, the HCDR2 comprises the amino acid sequence of SEQ ID NO:        130, the HCDR3 comprises the amino acid sequence of SEQ ID NO:        131, the LCDR1 comprises the amino acid sequence of SEQ ID NO:        145, the LCDR2 comprises the amino acid sequence of SEQ ID NO:        146, and the LCDR3 comprises the amino acid sequence of SEQ ID        NO: 147; or    -   (iv) the HCDR1 comprises the amino acid sequence of SEQ ID NO:        132, the HCDR2 comprises the amino acid sequence of SEQ ID NO:        133, the HCDR3 comprises the amino acid sequence of SEQ ID NO:        134, the LCDR1 comprises the amino acid sequence of SEQ ID NO:        148, the LCDR2 comprises the amino acid sequence of SEQ ID NO:        149, and the LCDR3 comprises the amino acid sequence of SEQ ID        NO: 150.

17. The binding agent of aspect 8, wherein

-   -   (i) the HCDR1 comprises the amino acid sequence of SEQ ID NO:        155, the HCDR2 comprises the amino acid sequence of SEQ ID NO:        156, the HCDR3 comprises the amino acid sequence of SEQ ID NO:        157, the LCDR1 comprises the amino acid sequence of SEQ ID NO:        171, the LCDR2 comprises the amino acid sequence of SEQ ID NO:        172, and the LCDR3 comprises the amino acid sequence of SEQ ID        NO: 173;    -   (ii) the HCDR1 comprises the amino acid sequence of SEQ ID NO:        158, the HCDR2 comprises the amino acid sequence of SEQ ID NO:        159, the HCDR3 comprises the amino acid sequence of SEQ ID NO:        160, the LCDR1 comprises the amino acid sequence of SEQ ID NO:        174, the LCDR2 comprises the amino acid sequence of SEQ ID NO:        175, and the LCDR3 comprises the amino acid sequence of SEQ ID        NO: 176;    -   (iii) the HCDR1 comprises the amino acid sequence of SEQ ID NO:        161, the HCDR2 comprises the amino acid sequence of SEQ ID NO:        162, the HCDR3 comprises the amino acid sequence of SEQ ID NO:        163, the LCDR1 comprises the amino acid sequence of SEQ ID NO:        177, the LCDR2 comprises the amino acid sequence of SEQ ID NO:        178, and the LCDR3 comprises the amino acid sequence of SEQ ID        NO: 179; or    -   (iv) the HCDR1 comprises the amino acid sequence of SEQ ID NO:        164, the HCDR2 comprises the amino acid sequence of SEQ ID NO:        165, the HCDR3 comprises the amino acid sequence of SEQ ID NO:        166, the LCDR1 comprises the amino acid sequence of SEQ ID NO:        180, the LCDR2 comprises the amino acid sequence of SEQ ID NO:        181, and the LCDR3 comprises the amino acid sequence of SEQ ID        NO: 182.

18. The binding agent of aspect 8, wherein

-   -   (i) the HCDR1 comprises the amino acid sequence of SEQ ID NO:        187, the HCDR2 comprises the amino acid sequence of SEQ ID NO:        188, the HCDR3 comprises the amino acid sequence of SEQ ID NO:        189, the LCDR1 comprises the amino acid sequence of SEQ ID NO:        203, the LCDR2 comprises the amino acid sequence of SEQ ID NO:        204, and the LCDR3 comprises the amino acid sequence of SEQ ID        NO: 205;    -   (ii) the HCDR1 comprises the amino acid sequence of SEQ ID NO:        190, the HCDR2 comprises the amino acid sequence of SEQ ID NO:        191, the HCDR3 comprises the amino acid sequence of SEQ ID NO:        192, the LCDR1 comprises the amino acid sequence of SEQ ID NO:        206, the LCDR2 comprises the amino acid sequence of SEQ ID NO:        207, and the LCDR3 comprises the amino acid sequence of SEQ ID        NO: 208;    -   (iii) the HCDR1 comprises the amino acid sequence of SEQ ID NO:        193, the HCDR2 comprises the amino acid sequence of SEQ ID NO:        194, the HCDR3 comprises the amino acid sequence of SEQ ID NO:        195, the LCDR1 comprises the amino acid sequence of SEQ ID NO:        209, the LCDR2 comprises the amino acid sequence of SEQ ID NO:        210, and the LCDR3 comprises the amino acid sequence of SEQ ID        NO: 211; or    -   (iv) the HCDR1 comprises the amino acid sequence of SEQ ID NO:        196, the HCDR2 comprises the amino acid sequence of SEQ ID NO:        197, the HCDR3 comprises the amino acid sequence of SEQ ID NO:        198, the LCDR1 comprises the amino acid sequence of SEQ ID NO:        212, the LCDR2 comprises the amino acid sequence of SEQ ID NO:        213, and the LCDR3 comprises the amino acid sequence of SEQ ID        NO: 214.

19. The binding agent of aspect 8, wherein

-   -   (i) the HCDR1 comprises the amino acid sequence of SEQ ID NO:        219, the HCDR2 comprises the amino acid sequence of SEQ ID NO:        220, the HCDR3 comprises the amino acid sequence of SEQ ID NO:        221, the LCDR1 comprises the amino acid sequence of SEQ ID NO:        235, the LCDR2 comprises the amino acid sequence of SEQ ID NO:        236, and the LCDR3 comprises the amino acid sequence of SEQ ID        NO: 237;    -   (ii) the HCDR1 comprises the amino acid sequence of SEQ ID NO:        222, the HCDR2 comprises the amino acid sequence of SEQ ID NO:        223, the HCDR3 comprises the amino acid sequence of SEQ ID NO:        224, the LCDR1 comprises the amino acid sequence of SEQ ID NO:        238, the LCDR2 comprises the amino acid sequence of SEQ ID NO:        239, and the LCDR3 comprises the amino acid sequence of SEQ ID        NO: 240;    -   (iii) the HCDR1 comprises the amino acid sequence of SEQ ID NO:        225, the HCDR2 comprises the amino acid sequence of SEQ ID NO:        226, the HCDR3 comprises the amino acid sequence of SEQ ID NO:        227, the LCDR1 comprises the amino acid sequence of SEQ ID NO:        241, the LCDR2 comprises the amino acid sequence of SEQ ID NO:        242, and the LCDR3 comprises the amino acid sequence of SEQ ID        NO: 243; or    -   (iv) the HCDR1 comprises the amino acid sequence of SEQ ID NO:        228, the HCDR2 comprises the amino acid sequence of SEQ ID NO:        229, the HCDR3 comprises the amino acid sequence of SEQ ID NO:        230, the LCDR1 comprises the amino acid sequence of SEQ ID NO:        244, the LCDR2 comprises the amino acid sequence of SEQ ID NO:        245, and the LCDR3 comprises the amino acid sequence of SEQ ID        NO: 246.

20. The binding agent of aspect 8, wherein

-   -   (i) the HCDR1 comprises the amino acid sequence of SEQ ID NO:        251, the HCDR2 comprises the amino acid sequence of SEQ ID NO:        252, the HCDR3 comprises the amino acid sequence of SEQ ID NO:        253, the LCDR1 comprises the amino acid sequence of SEQ ID NO:        267, the LCDR2 comprises the amino acid sequence of SEQ ID NO:        268, and the LCDR3 comprises the amino acid sequence of SEQ ID        NO: 269;    -   (ii) the HCDR1 comprises the amino acid sequence of SEQ ID NO:        254, the HCDR2 comprises the amino acid sequence of SEQ ID NO:        255, the HCDR3 comprises the amino acid sequence of SEQ ID NO:        256, the LCDR1 comprises the amino acid sequence of SEQ ID NO:        270, the LCDR2 comprises the amino acid sequence of SEQ ID NO:        271, and the LCDR3 comprises the amino acid sequence of SEQ ID        NO: 272;    -   (iii) the HCDR1 comprises the amino acid sequence of SEQ ID NO:        257, the HCDR2 comprises the amino acid sequence of SEQ ID NO:        258, the HCDR3 comprises the amino acid sequence of SEQ ID NO:        259, the LCDR1 comprises the amino acid sequence of SEQ ID NO:        273, the LCDR2 comprises the amino acid sequence of SEQ ID NO:        274, and the LCDR3 comprises the amino acid sequence of SEQ ID        NO: 275; or    -   (iv) the HCDR1 comprises the amino acid sequence of SEQ ID NO:        260, the HCDR2 comprises the amino acid sequence of SEQ ID NO:        261, the HCDR3 comprises the amino acid sequence of SEQ ID NO:        262, the LCDR1 comprises the amino acid sequence of SEQ ID NO:        276, the LCDR2 comprises the amino acid sequence of SEQ ID NO:        277, and the LCDR3 comprises the amino acid sequence of SEQ ID        NO: 278.

21. The binding agent of aspect 8, wherein

-   -   a) the HCDR1 comprises the amino acid sequence of SEQ ID NO:        283, the HCDR2 comprises the amino acid sequence of SEQ ID NO:        284, the HCDR3 comprises the amino acid sequence of SEQ ID NO:        285, the LCDR1 comprises the amino acid sequence of SEQ ID NO:        299, the LCDR2 comprises the amino acid sequence of SEQ ID NO:        300, and the LCDR3 comprises the amino acid sequence of SEQ ID        NO: 301;    -   b) the HCDR1 comprises the amino acid sequence of SEQ ID NO:        286, the HCDR2 comprises the amino acid sequence of SEQ ID NO:        287, the HCDR3 comprises the amino acid sequence of SEQ ID NO:        288, the LCDR1 comprises the amino acid sequence of SEQ ID NO:        302, the LCDR2 comprises the amino acid sequence of SEQ ID NO:        303, and the LCDR3 comprises the amino acid sequence of SEQ ID        NO: 304;    -   c) the HCDR1 comprises the amino acid sequence of SEQ ID NO:        289, the HCDR2 comprises the amino acid sequence of SEQ ID NO:        290, the HCDR3 comprises the amino acid sequence of SEQ ID NO:        291, the LCDR1 comprises the amino acid sequence of SEQ ID NO:        305, the LCDR2 comprises the amino acid sequence of SEQ ID NO:        306, and the LCDR3 comprises the amino acid sequence of SEQ ID        NO: 307; or    -   d) the HCDR1 comprises the amino acid sequence of SEQ ID NO:        292, the HCDR2 comprises the amino acid sequence of SEQ ID NO:        293, the HCDR3 comprises the amino acid sequence of SEQ ID NO:        294, the LCDR1 comprises the amino acid sequence of SEQ ID NO:        308, the LCDR2 comprises the amino acid sequence of SEQ ID NO:        309, and the LCDR3 comprises the amino acid sequence of SEQ ID        NO: 310.

22. The binding agent of aspect 8, wherein

-   -   a) the HCDR1 comprises the amino acid sequence of SEQ ID NO:        315, the HCDR2 comprises the amino acid sequence of SEQ ID NO:        316, the HCDR3 comprises the amino acid sequence of SEQ ID NO:        317, the LCDR1 comprises the amino acid sequence of SEQ ID NO:        331, the LCDR2 comprises the amino acid sequence of SEQ ID NO:        332, and the LCDR3 comprises the amino acid sequence of SEQ ID        NO: 333;    -   b) the HCDR1 comprises the amino acid sequence of SEQ ID NO:        318, the HCDR2 comprises the amino acid sequence of SEQ ID NO:        319, the HCDR3 comprises the amino acid sequence of SEQ ID NO:        320, the LCDR1 comprises the amino acid sequence of SEQ ID NO:        334, the LCDR2 comprises the amino acid sequence of SEQ ID NO:        335, and the LCDR3 comprises the amino acid sequence of SEQ ID        NO: 336;    -   c) the HCDR1 comprises the amino acid sequence of SEQ ID NO:        321, the HCDR2 comprises the amino acid sequence of SEQ ID NO:        322, the HCDR3 comprises the amino acid sequence of SEQ ID NO:        323, the LCDR1 comprises the amino acid sequence of SEQ ID NO:        337, the LCDR2 comprises the amino acid sequence of SEQ ID NO:        338, and the LCDR3 comprises the amino acid sequence of SEQ ID        NO: 339; or    -   d) the HCDR1 comprises the amino acid sequence of SEQ ID NO:        324, the HCDR2 comprises the amino acid sequence of SEQ ID NO:        325, the HCDR3 comprises the amino acid sequence of SEQ ID NO:        326, the LCDR1 comprises the amino acid sequence of SEQ ID NO:        340, the LCDR2 comprises the amino acid sequence of SEQ ID NO:        341, and the LCDR3 comprises the amino acid sequence of SEQ ID        NO: 342.

23. The binding agent of aspect 8, wherein

-   -   a) the VH comprises the amino acid sequence of SEQ ID NO: 39 and        the VL comprises the amino acid sequence of SEQ ID NO: 55;    -   b) the VH comprises the amino acid sequence of SEQ ID NO: 71 and        the VL comprises the amino acid sequence of SEQ ID NO: 87;    -   c) the VH comprises the amino acid sequence of SEQ ID NO: 103        and the VL comprises the amino acid sequence of SEQ ID NO: 119;    -   d) the VH comprises the amino acid sequence of SEQ ID NO: 135        and the VL comprises the amino acid sequence of SEQ ID NO: 151;    -   e) the VH comprises the amino acid sequence of SEQ ID NO: 167        and the VL comprises the amino acid sequence of SEQ ID NO: 183;    -   f) the VH comprises the amino acid sequence of SEQ ID NO: 199        and the VL comprises the amino acid sequence of SEQ ID NO: 215;    -   g) the VH comprises the amino acid sequence of SEQ ID NO: 231        and the VL comprises the amino acid sequence of SEQ ID NO: 247;    -   h) the VH comprises the amino acid sequence of SEQ ID NO: 263        and the VL comprises the amino acid sequence of SEQ ID NO: 279;    -   i) the VH comprises the amino acid sequence of SEQ ID NO: 295        and the VL comprises the amino acid sequence of SEQ ID NO: 311;        or    -   j) the VH comprises the amino acid sequence of SEQ ID NO: 327        and the VL comprises the amino acid sequence of SEQ ID NO: 343.

24. The binding agent of aspect 8, which is an antibody comprising aheavy chain and a light chain, wherein

-   -   a) the heavy chain comprises the amino acid sequence of SEQ ID        NO: 41 and the light chain comprises the amino acid sequence of        SEQ ID NO: 57;    -   b) the heavy chain comprises the amino acid sequence of SEQ ID        NO: 73 and the light chain comprises the amino acid sequence of        SEQ ID NO: 89;    -   c) the heavy chain comprises the amino acid sequence of SEQ ID        NO: 105 and the light chain comprises the amino acid sequence of        SEQ ID NO: 121;    -   d) the heavy chain comprises the amino acid sequence of SEQ ID        NO: 137 and the light chain comprises the amino acid sequence of        SEQ ID NO: 153;    -   e) the heavy chain comprises the amino acid sequence of SEQ ID        NO: 169 and the light chain comprises the amino acid sequence of        SEQ ID NO: 185;    -   f) the heavy chain comprises the amino acid sequence of SEQ ID        NO: 201 and the light chain comprises the amino acid sequence of        SEQ ID NO: 217;    -   g) the heavy chain comprises the amino acid sequence of SEQ ID        NO: 233 and the light chain comprises the amino acid sequence of        SEQ ID NO: 249;    -   h) the heavy chain comprises the amino acid sequence of SEQ ID        NO: 265 and the light chain comprises the amino acid sequence of        SEQ ID NO: 281;    -   i) the heavy chain comprises the amino acid sequence of SEQ ID        NO: 297 and the light chain comprises the amino acid sequence of        SEQ ID NO: 313; or    -   j) the heavy chain comprises the amino acid sequence of SEQ ID        NO: 329 and the light chain comprises the amino acid sequence of        SEQ ID NO: 345.

25. The binding agent of aspect 5, wherein the binding agent is anantibody or an antigen-binding fragment thereof, wherein the antibody orantigen-binding fragment comprises a VH and a VL, and wherein

-   -   a) the VH comprises an amino acid sequence that is at least 90%        or at least 95% identical to the amino acid sequence of SEQ ID        NO: 39 and the VL comprises an amino acid sequence that is at        least 90% or at least 95% identical to the amino acid sequence        of SEQ ID NO: 55;    -   b) the VH comprises an amino acid sequence that is at least 90%        or at least 95% identical to the amino acid sequence of SEQ ID        NO: 71 and the VL comprises the amino acid sequence of SEQ ID        NO: 87;    -   c) the VH comprises an amino acid sequence that is at least 90%        or at least 95% identical to the amino acid sequence of SEQ ID        NO: 103 and the VL comprises the amino acid sequence of SEQ ID        NO: 119;    -   d) the VH comprises an amino acid sequence that is at least 90%        or at least 95% identical to the amino acid sequence of SEQ ID        NO: 135 and the VL comprises an amino acid sequence that is at        least 90% or at least 95% identical to the amino acid sequence        of SEQ ID NO: 151;    -   e) the VH comprises an amino acid sequence that is at least 90%        or at least 95% identical to the amino acid sequence of SEQ ID        NO: 167 and the VL comprises an amino acid sequence that is at        least 90% or at least 95% identical to the amino acid sequence        of SEQ ID NO: 183;    -   f) the VH comprises an amino acid sequence that is at least 90%        or at least 95% identical to the amino acid sequence of SEQ ID        NO: 199 and the VL comprises an amino acid sequence that is at        least 90% or at least 95% identical to the amino acid sequence        of SEQ ID NO: 215;    -   g) the VH comprises an amino acid sequence that is at least 90%        or at least 95% identical to the amino acid sequence of SEQ ID        NO: 231 and the VL comprises an amino acid sequence that is at        least 90% or at least 95% identical to the amino acid sequence        of SEQ ID NO: 247;    -   h) the VH comprises an amino acid sequence that is at least 90%        or at least 95% identical to the amino acid sequence of SEQ ID        NO: 263 and the VL comprises an amino acid sequence that is at        least 90% or at least 95% identical to the amino acid sequence        of SEQ ID NO: 279;    -   i) the VH comprises an amino acid sequence that is at least 90%        or at least 95% identical to the amino acid sequence of SEQ ID        NO: 295 and the VL comprises an amino acid sequence that is at        least 90% or at least 95% identical to the amino acid sequence        of SEQ ID NO: 311; or    -   j) the VH comprises an amino acid sequence that is at least 90%        or at least 95% identical to the amino acid sequence of SEQ ID        NO: 327 and the VL comprises an amino acid sequence that is at        least 90% or at least 95% identical to the amino acid sequence        of SEQ ID NO: 343.

26. The binding agent of aspect 25, wherein the differences in aminoacid sequence is not within the complementarity determining regions.

27. The binding agent of aspect 8, wherein:

-   -   a. the HCDR1 comprises the amino acid sequence of SEQ ID NO: 27,        59, 91, 123, 155, 187, 219, 251, 283, or 315;    -   b. the HCDR2 comprises the amino acid sequence of SEQ ID NO: 28,        60, 92, 124, 156, 188, 220, 252, 284, or 316;    -   c. the HCDR3 comprises the amino acid sequence of SEQ ID NO: 29,        61, 93, 125, 157, 189, 221, 253, 285, or 317;    -   d. the LCDR1 comprises the amino acid sequence of SEQ ID NO: 43,        75, 107, 139, 171, 203, 235, 267, 299, or 331;    -   e. the LCDR2 comprises the amino acid sequence of SEQ ID NO: 44,        76, 108, 140, 172, 204, 236, 268, 300, or 332; and    -   f. the LCDR3 comprises the amino acid sequence of SEQ ID NO: 45,        77, 109, 141, 173, 205, 237, 269, 301, or 333.

28. The binding agent of aspect 8, wherein:

-   -   a. the HCDR1 comprises the amino acid sequence of SEQ ID NO: 30,        62, 94, 126, 158, 190, 222, 254, 286, or 318;    -   b. the HCDR2 comprises the amino acid sequence of SEQ ID NO: 31,        63, 95, 127, 159, 191, 223, 255, 287, or 319;    -   c. the HCDR3 comprises the amino acid sequence of SEQ ID NO: 32,        64, 96, 128, 160, 192, 224, 256, 288, or 320;    -   d. the LCDR1 comprises the amino acid sequence of SEQ ID NO: 46,        78, 110, 142, 174, 206, 238, 270, 302, or 334;    -   e. the LCDR2 comprises the amino acid sequence of SEQ ID NO: 47,        79, 111, 143, 175, 207, 239, 271, 303, or 335; and    -   f. the LCDR3 comprises the amino acid sequence of SEQ ID NO: 48,        80, 112, 144, 176, 208, 240, 272, 304, or 336.

29. The binding agent of any one of the preceding aspects, wherein thebinding agent is an antibody Fab fragment.

30. The binding agent of any one of the preceding aspects, wherein thebinding agent is a monoclonal human antibody.

31. A polynucleotide comprising nucleotide sequences encoding thebinding agent of any one of the preceding aspects.

32. A vector comprising the polynucleotide of aspect 31.

33. A host cell comprising the polynucleotide of aspect 31.

34. A host cell comprising the vector of aspect 32.

35. A method of producing a binding agent, said method comprisesculturing the host cell of aspect 33 or 34 under suitable conditions forexpression of the binding agent or a portion thereof, wherein the methodoptionally comprises purifying the binding agent.

36. A pharmaceutical composition comprising the binding agent of any oneof aspects 1-30.

37. A pharmaceutical composition for use as a medicament reversing theanticoagulant effect of an anti-FXI/FXIa antibody in a patient beingtreated with the anti-Factor XI/Factor XIa antibody, wherein thepharmaceutical composition comprises an effective amount of the bindingagent of any one of aspects 1-30.

38. A method for reversing the anticoagulant effect of an anti-FXI/FXIaantibody in a patient being treated with the anti-FXI/FXIa antibody orantigen-binding fragment thereof, comprising administering an effectiveamount of the binding agent of any one of aspects 1-30 to a patient inneed thereof.

39. The method of aspect 38, wherein the anti-FXI/FXIa antibody orantigen-binding fragment thereof comprises (i) a VH comprising the aminoacid sequence of SEQ ID NO: 12 and a VL comprising the amino acidsequence of SEQ ID NO: 23; or (ii) a heavy chain comprising the aminoacid sequence of SEQ ID NO: 14 and a light chain comprising the aminoacid sequence of SEQ ID NO: 25.

40. The method of aspect 38, wherein the anti-FXI/FXIa antibody orantigen-binding fragment thereof comprises (i) a VH comprisingcomplementarity determining regions HCDR1, HCDR2 and HCDR3 of a VHcomprising the amino acid sequence of SEQ ID NO: 12 and (ii) a VLcomprising complementarity determining regions LCDR1, LCDR2, and LCDR3of a VL comprising the amino acid sequence of SEQ ID NO: 23.

41. The method of aspect 38, wherein the anti-FXI/FXIa antibody orantigen-binding fragment thereof comprises:

-   -   (A)(i) a VH comprising complementarity determining regions        HCDR1, HCDR2 and HCDR3 comprising the amino acid sequences of        SEQ ID NO: 3, SEQ ID NO: 4, and SEQ ID NO: 5, respectively;        and (ii) a VL comprising complementarity determining regions        LCDR1, LCDR2, and LCDR3 comprising the amino acid sequence of        SEQ ID NO: 16, SEQ ID NO: 17, and SEQ ID NO: 18, respectively;    -   (B)(i) a VH comprising complementarity determining regions        HCDR1, HCDR2 and HCDR3 comprising the amino acid sequences of        SEQ ID NO: 6, SEQ ID NO: 4, and SEQ ID NO: 5, respectively;        and (ii) a VL comprising complementarity determining regions        LCDR1, LCDR2, and LCDR3 comprising the amino acid sequence of        SEQ ID NO: 16, SEQ ID NO: 17, and SEQ ID NO: 18, respectively;    -   (C)(i) a VH comprising complementarity determining regions        HCDR1, HCDR2 and HCDR3 comprising the amino acid sequences of        SEQ ID NO: 7, SEQ ID NO: 8, and SEQ ID NO: 5, respectively;        and (ii) a VL comprising complementarity determining regions        LCDR1, LCDR2, and LCDR3 comprising the amino acid sequence of        SEQ ID NO: 19, SEQ ID NO: 20, and SEQ ID NO: 21, respectively;        or    -   (D)(i) a VH comprising complementarity determining regions        HCDR1, HCDR2 and HCDR3 comprising the amino acid sequences of        SEQ ID NO: 9, SEQ ID NO: 10, and SEQ ID NO: 11, respectively;        and (ii) a VL comprising complementarity determining regions        LCDR1, LCDR2, and LCDR3 comprising the amino acid sequence of        SEQ ID NO: 22, SEQ ID NO: 20, and SEQ ID NO: 18, respectively.

42. The method of aspect 38, wherein the anti-FXI/FXIa antibody competeswith, or binds to the same epitope as, a reference anti-FXI/FXIaantibody comprising a heavy chain comprising the amino acid sequence ofSEQ ID NO: 14 and a light chain comprising the amino acid sequence ofSEQ ID NO: 25.

43. The method of aspect 38, wherein the anti-FXI/FXIa antibody binds anepitope of human FXI and/or FXIa comprising one, two, three, four, five,six, seven, eight, nine, ten, eleven, twelve, thirteen, fourteen,fifteen or more, or all of, amino acid residues selected from: Pro410,Arg413, Leu415, Cys416, His431, Cys432, Tyr434, Gly435, Glu437, Tyr472,Lys473, Met474, Ala475, Glu476, Tyr521, Arg522, Lys523, Leu524, Arg525,Asp526, Lys527, Arg548, His552, Ser575, Ser594, Trp595, Gly596, Glu597,Arg602, Glu603, and Arg604.

44. The method of any one of aspects 38-43, wherein the method furthercomprises applying one of the following to the patient: (i) fluidreplacement using colloids, crystalloids, human plasma or plasmaproteins such as albumin; (ii) transfusion with packed red blood orwhole blood; or (iii) administration of fresh frozen plasma (FFP),prothrombin complex concentrates (PCC), activated PCC (APCC), such as,factor VIII inhibitor, and/or recombinant, activated factor VII.

45. The method of any one of aspects 38-44, wherein the patient has oris at risk of developing thrombosis.

46. The method of any one of aspects 38-45, wherein the patient has

-   -   a. atrial fibrillation;    -   b. suspected or confirmed cardiac arrhythmia such as paroxysmal,        persistent or permanent atrial fibrillation or atrial flutter;    -   c. Chronic Thromboembolic Pulmonary Hypertension (CTEPH);    -   d. valvular heart disease with or without atrial fibrillation;    -   e. pulmonary hypertension;    -   f. congenital or acquired thrombophilia including but not        exclusively factor V Leiden, prothrombin mutation, antithrombin        III, protein C and protein S deficiencies, factor XIII mutation,        familial dysfibrinogenemia, congenital deficiency of        plasminogen, increased levels of factor XI, sickle cell disease,        antiphospholipid syndrome, autoimmune disease, chronic bowel        disease, nephrotic syndrome, hemolytic uremia,        myeloproliferative disease, disseminated intra vascular        coagulation, paroxysmal nocturnal hemoglobinuria and heparin        induced thrombopenia; or    -   g. chronic kidney disease.

47. The method of any one of aspects 38-45, wherein the patient hasnon-valvular atrial fibrillation.

48. The method of any one of aspects 38-47, wherein the patient has ademonstrated high risk of bleeding.

49. The method of any one of aspects 38-48, wherein the patient haschronic kidney disease.

50. The method of aspect 49, wherein patient has end stage renal disease(ESRD).

51. The method of aspect 50, wherein the patient has ESRD and isundergoing dialysis.

52. The method of aspect 51, wherein the patient has non-valvular atrialfibrillation.

53. The method of any one of aspects 38-52, wherein the patient is beingadministered the anti-FXI/FXIa antibody or antigen-binding fragmentthereof to reduce the risk of stroke and/or systemic embolism.

54. The method of any one of aspects 38-53, wherein reversal of theanticoagulant effect of the anti-FXI/FXIa antibody or antigen-bindingfragment thereof is needed for emergency surgery/urgent procedures andin life-threatening or uncontrolled bleeding.

55. An anti-idiotype antibody that specifically binds to ananti-FXI/FXIa antibody that binds within the catalytic domain ofFXI/FXIa.

56. The anti-idiotype antibody of aspect 55, wherein the anti-FXI/FXIaantibody binds to one or more epitopes of anti-FXI and/or FXIa, whereinthe epitope comprises two or more amino acid residues of Pro410, Arg413,Leu415, Cys416, His431, Cys432, Tyr434, Gly435, Glu437, Tyr472, Lys473,Met474, Ala475, Glu476, Tyr521, Arg522, Lys523, Leu524, Arg525, Asp526,Lys527, Arg548, His552, Ser575, Ser594, Trp595, Gly596, Glu597, Arg602,Glu603, and Arg604.

57. The anti-idiotype antibody of aspect 56, wherein the epitopecomprises four or more amino acid residues of Pro410, Arg413, Leu415,Cys416, His431, Cys432, Tyr434, Gly435, Glu437, Tyr472, Lys473, Met474,Ala475, Glu476, Tyr521, Arg522, Lys523, Leu524, Arg525, Asp526, Lys527,Arg548, His552, Ser575, Ser594, Trp595, Gly596, Glu597, Arg602, Glu603,and Arg604.

58. The anti-idiotype antibody of aspect 56, wherein the epitopecomprises six or more amino acid residues of Pro410, Arg413, Leu415,Cys416, His431, Cys432, Tyr434, Gly435, Glu437, Tyr472, Lys473, Met474,Ala475, Glu476, Tyr521, Arg522, Lys523, Leu524, Arg525, Asp526, Lys527,Arg548, His552, Ser575, Ser594, Trp595, Gly596, Glu597, Arg602, Glu603,and Arg604.

59. The anti-idiotype antibody of aspect 56, wherein the epitopecomprises eight or more amino acid residues of Pro410, Arg413, Leu415,Cys416, His431, Cys432, Tyr434, Gly435, Glu437, Tyr472, Lys473, Met474,Ala475, Glu476, Tyr521, Arg522, Lys523, Leu524, Arg525, Asp526, Lys527,Arg548, His552, Ser575, Ser594, Trp595, Gly596, Glu597, Arg602, Glu603,and Arg604.

60. The anti-idiotype antibody of aspect 56, wherein the epitopecomprises the residues of Pro410, Arg413, Leu415, Cys416, His431,Cys432, Tyr434, Gly435, Glu437, Tyr472, Lys473, Met474, Ala475, Glu476,Tyr521, Arg522, Lys523, Leu524, Arg525, Asp526, Lys527, Arg548, His552,Ser575, Ser594, Trp595, Gly596, Glu597, Arg602, Glu603, and Arg604.

61. The anti-idiotype antibody of aspect 56, wherein the epitopecomprises amino acid residues of Pro410, Arg413, Lys527 and one or moreamino acid residues of Leu415, Cys416, His431, Cys432, Tyr434, Gly435,Glu437, Tyr472, Lys473, Met474, Ala475, Glu476, Tyr521, Arg522, Lys523,Leu524, Arg525, Asp526, Arg548, His552, Ser575, Ser594, Trp595, Gly596,Glu597, Arg602, Glu603, and Arg604.

62. The anti-idiotype antibody of aspect 56, wherein the epitopecomprises amino acid residues of Pro410, Arg413, Lys527 and four or moreamino acid residues of Leu415, Cys416, His431, Cys432, Tyr434, Gly435,Glu437, Tyr472, Lys473, Met474, Ala475, Glu476, Tyr521, Arg522, Lys523,Leu524, Arg525, Asp526, Arg548, His552, Ser575, Ser594, Trp595, Gly596,Glu597, Arg602, Glu603, and Arg604.

63. The anti-idiotype antibody of aspect 56, wherein the epitopecomprises amino acid residues of Pro410, Arg413, Lys527 and six or moreamino acid residues of Leu415, Cys416, His431, Cys432, Tyr434, Gly435,Glu437, Tyr472, Lys473, Met474, Ala475, Glu476, Tyr521, Arg522, Lys523,Leu524, Arg525, Asp526, Arg548, His552, Ser575, Ser594, Trp595, Gly596,Glu597, Arg602, Glu603, and Arg604.

64. The anti-idiotype antibody of aspect 55, wherein the anti-FXI/FXIaantibody is NOV1401 or comprises the heavy chain variable region CDRsand light chain variable region CDRs of NOV1401.

65. The anti-idiotype antibody of aspect 55, wherein the anti-FXI/FXIaantibody binds to the same epitope of FXI/FXIa as NOV1401, or competesfor binding to FXI/FXIa with NOV1401.

66. The anti-idiotype antibody of any one of aspects 55-65, which blocksthe anti-FXI/FXIa antibody from binding to FXI/FXIa.

67. The anti-idiotype antibody of any one of aspects 55-66, wherein theanti-idiotype antibody reverses or inhibits the anti-FXI/FXIa antibody'santi-coagulant effects.

68. A method of managing bleeding or bleeding risk in a patient treatedor administered an anti-FXI/FXIa antibody, comprising the step ofadministering to the patient in need thereof, an anti-idiotype antibodyof the anti-FXI/FXIa antibody, wherein the anti-idiotype antibodyspecifically binds to the anti-FXI/FXIa antibody and blocks theanti-FXI/FXIa antibody from binding to FXI/FXIa.

69. The method of aspect 68, wherein the anti-FXI/FXIa antibody isNOV1401 or comprises the heavy chain variable region CDRs and lightchain variable region CDRs of NOV1401.

70. The method of aspect 68, wherein the anti-FXI/FXIa antibody binds tothe same epitope of FXI/FXIa as NOV1401, or competes for binding toFXI/FXIa with NOV1401.

71. The method of aspect 68, wherein the anti-FXI/FXIa antibody bindswithin the catalytic domain of FXI/FXIa.

72. The method of aspect 71, wherein the anti-FXI/FXIa antibody binds toone or more epitopes of FXI and/or FXIa, wherein the epitope comprisestwo or more amino acid residues of Pro410, Arg413, Leu415, Cys416,His431, Cys432, Tyr434, Gly435, Glu437, Tyr472, Lys473, Met474, Ala475,Glu476, Tyr521, Arg522, Lys523, Leu524, Arg525, Asp526, Lys527, Arg548,His552, Ser575, Ser594, Trp595, Gly596, Glu597, Arg602, Glu603, andArg604.

73. The method of aspect 72, wherein the epitope comprises four or moreamino acid residues of Pro410, Arg413, Leu415, Cys416, His431, Cys432,Tyr434, Gly435, Glu437, Tyr472, Lys473, Met474, Ala475, Glu476, Tyr521,Arg522, Lys523, Leu524, Arg525, Asp526, Lys527, Arg548, His552, Ser575,Ser594, Trp595, Gly596, Glu597, Arg602, Glu603, and Arg604.

74. The method of aspect 72, wherein the epitope comprises six or moreamino acid residues of Pro410, Arg413, Leu415, Cys416, His431, Cys432,Tyr434, Gly435, Glu437, Tyr472, Lys473, Met474, Ala475, Glu476, Tyr521,Arg522, Lys523, Leu524, Arg525, Asp526, Lys527, Arg548, His552, Ser575,Ser594, Trp595, Gly596, Glu597, Arg602, Glu603, and Arg604.

75. The method of aspect 72, wherein the epitope comprises eight or moreamino acid residues of Pro410, Arg413, Leu415, Cys416, His431, Cys432,Tyr434, Gly435, Glu437, Tyr472, Lys473, Met474, Ala475, Glu476, Tyr521,Arg522, Lys523, Leu524, Arg525, Asp526, Lys527, Arg548, His552, Ser575,Ser594, Trp595, Gly596, Glu597, Arg602, Glu603, and Arg604.

76. The method of aspect 72, wherein the epitope comprises the residuesof Pro410, Arg413, Leu415, Cys416, His431, Cys432, Tyr434, Gly435,Glu437, Tyr472, Lys473, Met474, Ala475, Glu476, Tyr521, Arg522, Lys523,Leu524, Arg525, Asp526, Lys527, Arg548, His552, Ser575, Ser594, Trp595,Gly596, Glu597, Arg602, Glu603, and Arg604.

77. The method of aspect 72, wherein the epitope comprises amino acidresidues of Pro410, Arg413, Lys527 and one or more amino acid residuesof Leu415, Cys416, His431, Cys432, Tyr434, Gly435, Glu437, Tyr472,Lys473, Met474, Ala475, Glu476, Tyr521, Arg522, Lys523, Leu524, Arg525,Asp526, Arg548, His552, Ser575, Ser594, Trp595, Gly596, Glu597, Arg602,Glu603 and Arg604.

78. The method of aspect 72, wherein the epitope comprises amino acidresidues of Pro410, Arg413, Lys527 and four or more amino acid residuesof Leu415, Cys416, His431, Cys432, Tyr434, Gly435, Glu437, Tyr472,Lys473, Met474, Ala475, Glu476, Tyr521, Arg522, Lys523, Leu524, Arg525,Asp526, Arg548, His552, Ser575, Ser594, Trp595, Gly596, Glu597, Arg602,Glu603, and Arg604.

79. The method of aspect 72, wherein the epitope comprises amino acidresidues of Pro410, Arg413, Lys527 and six or more amino acid residuesof Leu415, Cys416, His431, Cys432, Tyr434, Gly435, Glu437, Tyr472,Lys473, Met474, Ala475, Glu476, Tyr521, Arg522, Lys523, Leu524, Arg525,Asp526, Arg548, His552, Ser575, Ser594, Trp595, Gly596, Glu597, Arg602,Glu603, and Arg604.

80. The method of any one of aspect 68-79, wherein the anti-idiotypeantibody or antigen binding fragment thereof reverses the effects of theanti-FXI/FXIa antibody.

81. The method of any one of aspect 68-80, wherein the anti-idiotypeantibody or antigen binding fragment thereof reverses or inhibitsanti-coagulant effects of the anti-FXI/FXIa antibody.

82. A method of managing bleeding or bleeding risk in a patient treatedor administered an anti-FXI/FXIa antibody, comprising the step ofadministering to the patient in need thereof, an anti-idiotype antibodyof the anti-FXI/FXIa antibody, wherein the anti-idiotype antibody orantigen binding fragment thereof specifically binds to theantigen-binding region of the anti-FXI/FXIa antibody and blocks theanti-FXI/FXIa antibody from binding to FXI and/or FXIa, and wherein theanti-FXI/FXIa antibody is NOV1401.

83. The method of aspect 82, wherein the anti-idiotype antibody orantigen binding fragment thereof is a Fab.

84. The method of aspect 82 or 83, wherein the patient is diagnosed withatrial fibrillation and is being administered the anti-FXI/FXIa antibodyfor treating or preventing stroke associated with atrial fibrillation.

85. Use of the binding agent of any one of aspects 1-30 in thepreparation of a medicament for reversing the anticoagulant effect of ananti-FXI/FXIa antibody or for managing bleeding or bleeding risk, in apatient being treated with the anti-Factor XI/Factor XIa antibody,wherein the patient is being treated with the anti-Factor XI/Factor XIafor a thromboembolic disease or disorder.

86. The use of aspect 85, wherein the patient is diagnosed with atrialfibrillation, optionally with a high bleeding risk, and is beingadministered the anti-FXI/FXIa antibody to reduce the risk of strokeand/or systemic embolism.

BRIEF DESCRIPTION OF THE DRAWINGS

FIG. 1 shows representative binding curves from SET experiments for eachof the 10 anti-NOV1401 antibodies as described in Examples. K_(D) valueswere determined from fitting the experimental data to a 1:1 bindingmodel for Fabs as described in Examples. Average K_(D) values from twoto three individual experiments are shown.

FIG. 2 shows representative SPR response curves for binding of NOV1401and three NOV1401/anti-NOV1401 mixtures to immoblized FXIa. Increasingconcentrations of anti-NOV1401 reduce binding of NOV1401 to FXIa with a10 fold molar excess completely blocking the binding. These dataindicate that anti-NOV1401 is capable to bind to and block NOV1401 frominteracting with FXIa. Anti-NOV1401 alone did not show any binding toimmobilized FXIa (not shown).

FIG. 3 shows aPTT assay results for two representative anti-NOV1401 Fabswhen NOV1401 was preincubated for 10 min with anti-NOV1401 beforeFXI-containing human plasma was added and the intrinsic pathway of thecoagulation cascade was triggered. Both anti-NOV1401 Fabs block the aPTTprolonging effect of NOV1401 in a concentration-dependent manner, i.e.inhibit the effect of NOV1401. 100% inhibition (dotted line) wasachieved at 3× molar access of anti-NOV1401.

FIG. 4 shows aPTT assay results for 10 anti-NOV1401 Fabs when NOV1401was pre-incubated for 5 min with FXI-containing human plasma beforeanti-NOV1401 Fab was added and the intrinsic pathway of the coagulationcascade was triggered. All 10 anti-NOV1401 show aconcentration-dependent partial reversal of the effects of NOV1401 onaPTT.

FIG. 5 shows TGA results for 10 anti-NOV1401 Fabs when NOV1401 waspre-incubated for 5 min with FXI-containing human plasma beforeanti-NOV1401 Fab was added and the thrombin feedback loop was triggered.The TGA was conducted at a constant concentration for NOV1401 of 0.05which corresponds to the IC₅₀ value determined in a separate experiment.All 10 anti-NOV1401 Fabs show a concentration-dependent partial reversalof the effects of NOV1401 on thrombin generation.

FIG. 6 shows ex-vivo aPTT assay results from blood/plasma samples ofcynomolgus monkeys treated with a single 3 mg/kg subcutaneous dose ofNOV1401 on study day one followed by two i.v. doses of IDT3 on studydays 4 and 5, respectively.

DETAILED DESCRIPTION Terminology

Unless defined otherwise, all technical and scientific terms used hereinhave the same meaning as commonly understood by those of ordinary skillin the art to which this present disclosure pertains.

As used in the specification and claims, the singular form “a”, “an” and“the” include plural references unless the context clearly dictatesotherwise. For example, the term “a cell” includes a plurality of cells,including mixtures thereof.

All numerical designations, e.g., pH, temperature, time, concentration,and molecular weight, including ranges, are approximations which arevaried (+) or (−) by increments of 0.1. It is to be understood, althoughnot always explicitly stated that all numerical designations arepreceded by the term “about.” It also is to be understood, although notalways explicitly stated, that the reagents described herein are merelyexamples and that equivalents of such are known in the art.

The terms “binding agent,” “reversal agent,” and “antidote” are usedinterchangeably, and, in the context of an antibody which specificallybinds to Factor XI and/or Factor XIa (“anti-FXI/FXIa antibody”), referto a protein, polypeptide, or a complex thereof, such as ananti-idiotype antibody or a fragment thereof such as a Fab fragment, oran inactive FXI/FXIa-derived polypeptide or protein fragment thatspecifically binds to an anti-FXI/FXIa antibody, such as, theantigen-binding region(s) or variable region(s) of the anti-FXI/FXIaantibody. In specific aspects provided herein, the binding agent iscapable of reversing (e.g., partially reversing by at least 10%, atleast 20%, at least 30%, at least 40%, at least 50%, at least 60%, atleast 70%) one or more anticoagulant effects of the anti-FXI/FXIaantibody (e.g., antibody NOV1401). In further specific aspects providedherein, the binding agent is capable of blocking binding of ananti-FXI/FXIa antibody to its antigen, e.g., FXI/FXIa. In a specificaspect, as used herein, the terms “anti-NOV1401,” “anti-NOV1401antibody,” “anti-NOV1401 Fab,” “NOV1401 binding agent,” “NOV1401antidote,” and the likes, are used interchangeably and refer to abinding agent or reversal agent, such as an anti-idiotype antibody or afragment thereof, which specifically binds to anti-Factor XI antibodyNOV1401 (see Table 1). Non-limiting examples of NOV1401 binding/reversalagents are described herein, for example, Table 2.

The terms “anti-idiotype antibody,” “anti-Id antibody,” and“anti-idiotypic antibody” are used interchangeably, and refer to anantibody and fragments thereof (e.g., Fab fragment) that specificallybinds to the antigen-binding region(s) of another antibody.Anti-idiotype antibodies are typically raised against theantigen-binding region(s) or complementarity determining regions (CDRs)(idiotype) of a target antibody. Anti-Idiotype antibodies can beproduced by various methods described previously, see, e.g., Pan et al.,1995, FASEB J. 9:43-49.

The terms “FXI protein,” “FXI antigen,” and “FXI” are usedinterchangeably, and refer to the Factor XI protein in differentspecies. Factor XI is the mammalian plasma coagulation factor XI, aglycoprotein present in human plasma at a concentration of 25-30 nM as azymogen that when converted by limited proteolysis to an active serineprotease, participates in the intrinsic pathway of blood coagulation.

The terms “FXIa protein,” “FXIa antigen,” and “FXIa”, are usedinterchangeably, and refers to the activated FXI protein in differentspecies. The zymogen Factor XI is converted into its active form, thecoagulation factor Xla (FXIa), either via the contact phase of bloodcoagulation or through thrombin-mediated activation on the plateletsurface. During this activation of factor XI, an internal peptide bondis cleaved in each of the two chains, resulting in the activated factorXla, a serine protease composed of two heavy and two light chains heldtogether by disulfide bonds. This serine protease FXIa converts thecoagulation Factor IX into IXa, which subsequently activates coagulationFactor X (Xa). Xa then can mediate coagulation Factor 11/Thrombinactivation. For example, human FXI has the sequence as set out in Table1 (SEQ ID NO:1), and has been described in previous reports andliterature (Mandle R J Jr, et al. (1979) Blood; 54(4): 850; NCBIReference Sequence: AAA51985).

In the context of this disclosure, the terms “FXI” and “FXIa” (and thelike) include mutants and variants of the natural FXI and FXIa protein,respectively, which have substantially the same amino acid sequence asthat of the native primary structure (amino acid sequence) described inthe above-mentioned reports.

The term “catalytic domain,” “serine protease catalytic domain,” andsimilar terms as used herein in the context of FXI, means amino acidsIle370 to Val607, as counted from the Glu1 at the N-terminus of themature protein that is in circulation. It can also be described asresidues 388-625 at the C-terminus of FXI. As used herein, the term“active site” means the catalytic triad comprised of the amino acidsHis413, Asp462 and Se557. (Bane and Gailani (2014) Drug Disc. 19(9),which is incorporated by reference herein in its entirety).

The term “antibody” as used herein means a whole antibody and anyantigen binding fragment (i.e., “antigen-binding portion”) or singlechain thereof and is derived from an immunoglobulin molecule thatspecifically binds to an antigen. A whole antibody is a glycoproteincomprising at least two heavy (H) chains and two light (L) chainsinter-connected by disulfide bonds. Each heavy chain is comprised of aheavy chain variable region (abbreviated herein as VH) and a heavy chainconstant region. The heavy chain constant region is comprised of threedomains, CH1, CH2 and CH3. Each light chain is comprised of a lightchain variable region (abbreviated herein as VL) and a light chainconstant region. The light chain constant region is comprised of onedomain, CL. The VH and VL regions can be further subdivided into regionsof hypervariability, termed complementarity determining regions (CDR),interspersed with regions that are more conserved, termed frameworkregions (FR). Each VH and VL is composed of three CDRs and four FRsarranged from amino-terminus to carboxy-terminus in the following order:FR1, CDR1, FR2, CDR2, FR3, CDR3, FR4. The variable regions of the heavyand light chains contain a binding domain that interacts with anantigen. The constant regions of the antibodies may mediate the bindingof the immunoglobulin to host tissues or factors, including variouscells of the immune system (e.g., effector cells) and the firstcomponent (Clq) of the classical complement system. In some specificaspects, an antibody can be a monoclonal antibody, human antibody,humanized antibody, camelised antibody, or chimeric antibody. Antibodiescan be of any isotype (e.g., IgG, IgE, IgM, IgD, IgA and IgY), class(e.g., IgG1, IgG2, IgG3, IgG4, IgA1 and IgA2) or subclass.

The term “antigen binding portion” or “antigen binding fragment” of anantibody, as used herein, refers to one or more fragments of an intactantibody that retain the ability to specifically bind to a given antigen(e.g., anti-FXI/FXIa antibody, such as NOV1401). Antigen bindingfunctions of an antibody can be performed by fragments of an intactantibody. Examples of binding fragments encompassed within the termantigen binding portion or antigen binding fragment of an antibodyinclude a Fab fragment, a monovalent fragment consisting of the VL, VH,CL and CH1 domains; a F(ab)2 fragment, a bivalent fragment comprisingtwo Fab fragments linked by a disulfide bridge at the hinge region; anFd fragment consisting of the VH and CH1 domains; an Fv fragmentconsisting of the VL and VH domains of a single arm of an antibody; asingle domain antibody (dAb) fragment (Ward et al., 1989 Nature341:544-546), which consists of a VH domain or a VL domain; and anisolated complementarity determining region (CDR).

Furthermore, although the two domains of the Fv fragment, VL and VH, arecoded for by separate genes, they can be joined, using recombinantmethods, by an artificial peptide linker that enables them to be made asa single protein chain in which the VL and VH regions pair to formmonovalent molecules (known as single chain Fv (scFv); see, e.g., Birdet al., 1988 Science 242:423-426; and Huston et al., 1988 Proc. Natl.Acad. Sci. 85:5879-5883). Such single chain antibodies include one ormore antigen binding portions or fragments of an antibody. Theseantibody fragments are obtained using conventional techniques known tothose of skill in the art, and the fragments are screened for utility inthe same manner as are intact antibodies.

Antigen binding fragments can also be incorporated into single domainantibodies, maxibodies, minibodies, intrabodies, diabodies, triabodies,tetrabodies, v-NAR and bis-scFv (see, e.g., Hollinger and Hudson, 2005,Nature Biotechnology, 23, 9, 1126-1136). Antigen binding portions ofantibodies can be grafted into scaffolds based on polypeptides such asFibronectin type III (Fn3) (see U.S. Pat. No. 6,703,199, which describesfibronectin polypeptide monobodies).

Antigen binding fragments can be incorporated into single chainmolecules comprising a pair of tandem Fv segments (VH-CH1-VH-CH1) which,together with complementary light chain polypeptides, form a pair ofantigen binding regions (Zapata et al., 1995 Protein Eng.8(10):1057-1062; and U.S. Pat. No. 5,641,870).

As used herein, the term “affinity” refers to the strength ofinteraction between antibody and antigen at single antigenic sites.Within each antigenic site, the variable region of the antibody “arm”interacts through weak non-covalent forces with antigen at numeroussites; the more interactions, the stronger the affinity. As used herein,the term “high affinity” for an antibody or antigen binding fragmentsthereof (e.g., a Fab fragment) generally refers to an antibody, orantigen binding fragment, having a K_(D) of 10-9 M or less (e.g., aK_(D) of 10-10 M or less, a K_(D) of 10-11 M or less, a K_(D) of 10-12 Mor less, a K_(D) of 10-13 M or less, a K_(D) of 10-14 M or less, etc.).

The term “amino acid” refers to naturally occurring and synthetic aminoacids, as well as amino acid analogs and amino acid mimetics thatfunction in a manner similar to the naturally occurring amino acids.Naturally occurring amino acids are those encoded by the genetic code,as well as those amino acids that are later modified, e.g.,hydroxyproline, γ-carboxyglutamate, and O-phosphoserine. Amino acidanalogs refer to compounds that have the same basic chemical structureas a naturally occurring amino acid, i.e., an alpha carbon that is boundto a hydrogen, a carboxyl group, an amino group, and an R group, e.g.,homoserine, norleucine, methionine sulfoxide, methionine methylsulfonium. Such analogs have modified R groups (e.g., norleucine) ormodified peptide backbones, but retain the same basic chemical structureas a naturally occurring amino acid. Amino acid mimetics refers tochemical compounds that have a structure that is different from thegeneral chemical structure of an amino acid, but that functions in amanner similar to a naturally occurring amino acid.

The term “binding specificity” as used herein refers to the ability ofan individual antibody combining site to react with only one antigenicdeterminant.

As used herein, the terms “immunospecifically binds,”“immunospecifically recognizes,” “specifically binds,” and “specificallyrecognizes” are analogous terms in the context of antibodies and referto molecules that bind to an antigen (e.g., epitope or immune complex)as such binding is understood by one skilled in the art. For example, amolecule that specifically binds to an antigen may bind to otherpeptides or polypeptides, generally with lower affinity as determinedby, e.g., immunoassays, Biacore™, KinExA 3000 instrument (SapidyneInstruments, Boise, ID), or other assays known in the art. In a specificembodiment, molecules that immunospecifically bind to an antigen bind tothe antigen with a Ka that is at least 2 logs, 2.5 logs, 3 logs, 4 logsor greater than the Ka when the molecules bind to another antigen. Inanother specific embodiment, molecules that immunospecifically bind toan antigen do not cross react with other proteins.

The term “FXI and/or FXIa mediated” refers to the fact that FXI and/orFXIa mediates the intrinsic and/or common coagulation pathways bydirectly or indirectly activating Factor IX (also known as FIX), FactorX (FX), and/or thrombin, and/or by binding to platelet receptors.

The term “hemostasis” represents the principal mechanisms for arrestingthe flow of blood at sites of injury and restoring vascular patencyduring wound healing, respectively. During normal hemostasis andpathological thrombosis, three mechanisms become activatedsimultaneously: primary hemostasis meaning the interactions of activatedplatelets with the vessel wall, the formation of fibrin, and a processtermed as fibrinolysis.

The terms “coagulation and coagulation cascade,” “cascade model ofcoagulation,” and the like, refer to the protein based system whichserves to stabilize a clot that has formed to seal up a wound. Thecoagulation pathway is a proteolytic cascade. Each enzyme of the pathwayis present in the plasma as a Zymogen (in an inactive form), which onactivation undergoes proteolytic cleavage to release the active factorfrom the precursor molecule. The coagulation cascade functions as aseries of positive and negative feedback loops which control theactivation process. The ultimate goal of the pathway is to producethrombin, which can then convert soluble fibrinogen into fibrin thatforms a clot.

The process of generation of thrombin can be divided into three phases:the intrinsic and extrinsic pathways, which provide alternative routesfor the generation of an active clotting factor: FXa (ActivatedFactor-X), and the final common pathway, which results in thrombinformation (Hoffman M. M. and Monroe D. M. (2005) Curr Hematol Rep.4:391-396; Johne J, et al. (2006) Biol Chem. 387:173-178).

As used herein, the terms “manage,” “managing,” and “management” referto the beneficial effects that a subject derives from a therapy (e.g., aprophylactic or therapeutic agent), which does not result in a cure of adisease, disorder, or condition (e.g., thrombosis or thromboembolicdisorder). In certain embodiments, a subject is administered one or moretherapies (e.g., binding agent or antibody described herein) to “manage”thrombosis or thromboembolic disorder, one or more symptoms thereof, soas to prevent the progression or worsening of the condition or disorder.

“Platelet aggregation” refers to the process whereby when a break in ablood vessel occurs, substances are exposed that normally are not indirect contact with the blood flow. These substances (primarily collagenand von Willebrand factor) allow the platelets to adhere to the brokensurface. Once a platelet adheres to the surface, it releases chemicalsthat attract additional platelets to the damaged area, referred to asplatelet aggregation. These two processes are the first responses tostop bleeding.

A “thromboembolic disorder,” or similar terms as used herein, refer toany number of conditions or diseases in which the intrinsic and/orcommon coagulation pathways are aberrantly activated or are notnaturally deactivated (e.g., without therapeutic means). Theseconditions include but are not limited to thrombic stroke, atrialfibrillation, stroke prevention in atrial fibrillation (SPAF), deep veinthrombosis, venous thromboembolism, and pulmonary embolism. These canalso include catheter-related conditions (e.g., Hickman catheter inoncology patients) in which catheters become thrombosed, andextracorporeal membrane oxygenation (ECMO), in which the tubing developsclots.

A “thromboembolic,” or similar terms as used herein, can also refer toany number of the following, which the anti-FXI and/or FXIa Abs orantigen binding fragments thereof of the present disclosure can be usedto prevent or treat or to reduce the risk of:

-   -   thromboembolism in subjects with suspected or confirmed cardiac        arrhythmia such as paroxysmal, persistent or permanent atrial        fibrillation or atrial flutter;    -   stroke prevention in atrial fibrillation (SPAF), a subpopulation        of which is AF patients undergoing percutaneous coronary        interventions (PCI);    -   acute venous thromboembolic events (VTE) treatment and extended        secondary VTE prevention in patients at high risk for bleeding;    -   cerebral and cardiovascular events in secondary prevention after        transient ischemic attack (TIA) or non-disabling stroke and        prevention of thromboembolic events in heart failure with sinus        rhythm;    -   clot formation in left atrium and thromboembolism in subjects        undergoing cardioversion for cardiac arrhythmia;    -   thrombosis before, during and after ablation procedure for        cardiac arrhythmia;    -   venous thrombosis, this includes but not exclusively, treatment        and secondary prevention of deep or superficial veins thrombosis        in the lower members or upper member, thrombosis in the        abdominal and thoracic veins, sinus thrombosis and thrombosis of        jugular veins;    -   thrombosis on any artificial surface in the veins like catheter        or pacemaker wires;    -   pulmonary embolism in patients with or without venous        thrombosis;    -   Chronic Thromboembolic Pulmonary Hypertension (CTEPH);    -   arterial thrombosis on ruptured atherosclerotic plaque,        thrombosis on intra-arterial prosthesis or catheter and        thrombosis in apparently normal arteries, this includes but not        limited to acute coronary syndromes, ST elevation myocardial        infarction, non ST elevation myocardial infarction, unstable        angina, stent thrombosis, thrombosis of any artificial surface        in the arterial system and thrombosis of pulmonary arteries in        subjects with or without pulmonary hypertension;    -   thrombosis and thromboembolism in patients undergoing        percutaneous coronary interventions (PCI);    -   cardioembolic and cryptogenic strokes;    -   thrombosis in patients with invasive and non-invasive cancer        malignancies;    -   thrombosis over an indwelling catheter;    -   thrombosis and thromboembolism in severely ill patients;    -   cardiac thrombosis and thromboembolism, this includes but not        exclusively cardiac thrombosis after myocardial infarction,        cardiac thrombosis related to condition such as cardiac        aneurysm, myocardial fibrosis, cardiac enlargement and        insufficiency, myocarditis and artificial surface in the heart;    -   thromboembolism in patients with valvular heart disease with or        without atrial fibrillation;    -   thromboembolism over valvular mechanic or biologic prostheses;    -   thromboembolism in patients who had native or artificial cardiac        patches, arterial or venous conduit tubes after heart repair of        simple or complex cardiac malformations;    -   venous thrombosis and thromboembolism after knee replacement        surgery, hip replacement surgery, and orthopedic surgery,        thoracic or abdominal surgery;    -   arterial or venous thrombosis after neurosurgery including        intracranial and spinal cord interventions;    -   congenital or acquired thrombophilia including but not        exclusively factor V Leiden, prothrombin mutation, antithrombin        III, protein C and protein S deficiencies, factor XIII mutation,        familial dysfibrinogenemia, congenital deficiency of        plasminogen, increased levels of factor XI, sickle cell disease,        antiphospholipid syndrome, autoimmune disease, chronic bowel        disease, nephrotic syndrome, hemolytic uremia,        myeloproliferative disease, disseminated intra vascular        coagulation, paroxysmal nocturnal hemoglobinuria and heparin        induced thrombopenia;    -   thrombosis and thromboembolism in chronic kidney disease; and    -   thrombosis and thromboembolism in patients undergoing        hemodialysis and in patients undergoing extra-corporal membrane        oxygenation.

The term “chimeric antibody” is an antibody molecule in which (a) theconstant region, or a portion thereof, is altered, replaced or exchangedso that the antigen binding site (variable region) is linked to aconstant region of a different or altered class, effector functionand/or species, or an entirely different molecule which confers newproperties to the chimeric antibody, e.g., an enzyme, toxin, hormone,growth factor, drug, etc.; or (b) the variable region, or a portionthereof, is altered, replaced or exchanged with a variable region havinga different or altered antigen specificity. For example, a mouseantibody can be modified by replacing its constant region with theconstant region from a human immunoglobulin. Due to the replacement witha human constant region, the chimeric antibody can retain itsspecificity in recognizing the antigen while having reduced antigenicityin human as compared to the original mouse antibody.

The term “conservatively modified variant” applies to both amino acidand nucleic acid sequences. With respect to particular nucleic acidsequences, conservatively modified variants refers to those nucleicacids which encode identical or essentially identical amino acidsequences, or where the nucleic acid does not encode an amino acidsequence, to essentially identical sequences. Because of the degeneracyof the genetic code, a large number of functionally identical nucleicacids encode any given protein. For instance, the codons GCA, GCC, GCGand GCU all encode the amino acid alanine. Thus, at every position wherean alanine is specified by a codon, the codon can be altered to any ofthe corresponding codons described without altering the encodedpolypeptide. Such nucleic acid variations are “silent variations,” whichare one species of conservatively modified variations. Every nucleicacid sequence herein which encodes a polypeptide also describes everypossible silent variation of the nucleic acid. One of skill willrecognize that each codon in a nucleic acid (except AUG, which isordinarily the only codon for methionine, and TGG, which is ordinarilythe only codon for tryptophan) can be modified to yield a functionallyidentical molecule. Accordingly, each silent variation of a nucleic acidthat encodes a polypeptide is implicit in each described sequence.

For polypeptide sequences, “conservatively modified variants” includeindividual substitutions, deletions or additions to a polypeptidesequence which result in the substitution of an amino acid with achemically similar amino acid. Conservative substitution tablesproviding functionally similar amino acids are well known in the art.Such conservatively modified variants are in addition to and do notexclude polymorphic variants, interspecies homologs, and alleles of thepresent disclosure. The following eight groups contain amino acids thatare conservative substitutions for one another: 1) Alanine (A), Glycine(G); 2) Aspartic acid (D), Glutamic acid (E); 3) Asparagine (N),Glutamine (Q); 4) Arginine (R), Lysine (K); 5) Isoleucine (I), Leucine(L), Methionine (M), Valine (V); 6) Phenylalanine (F), Tyrosine (Y),Tryptophan (W); 7) Serine (S), Threonine (T); and 8) Cysteine (C),Methionine (M) (see, e.g., Creighton, Proteins (1984)). In someembodiments, the term “conservative sequence modifications” are used torefer to amino acid modifications that do not significantly affect oralter the binding characteristics of the antibody containing the aminoacid sequence.

The term “epitope” means a protein determinant capable of specificbinding to an antibody. Epitopes usually consist of chemically activesurface groupings of molecules such as amino acids or sugar side chainsand usually have specific three dimensional structural characteristics,as well as specific charge characteristics. Conformational andnonconformational epitopes are distinguished in that the binding to theformer but not the latter is lost in the presence of denaturingsolvents. Two antibodies are said to “compete” if one antibody is shownto bind the same epitope as the second antibody in a competitive bindingassay, by any of the methods well known to those of skill in the art.

The term “human antibody”, as used herein, is intended to includeantibodies having variable regions in which both the framework and CDRregions are derived from sequences of human origin. Furthermore, if theantibody contains a constant region, the constant region also is derivedfrom such human sequences, e.g., human germline sequences, or mutatedversions of human germline sequences. The human antibodies of thepresent disclosure may include amino acid residues not encoded by humansequences (e.g., mutations introduced by random or site-specificmutagenesis in vitro or by somatic mutation in vivo).

The term “human monoclonal antibody” refers to antibodies displaying asingle binding specificity which have variable regions in which both theframework and CDR regions are derived from human sequences. In oneembodiment, the human monoclonal antibodies are prepared using phagedisplay methods for screening libraries of human immunoglobulin genes.

A “humanized” antibody is an antibody that retains the reactivity of anon-human antibody while being less immunogenic in humans. This can beachieved, for instance, by retaining the non-human CDR regions andreplacing the remaining parts of the antibody with their humancounterparts (i.e., the constant region as well as the frameworkportions of the variable region). See, e.g., Morrison et al., Proc.Natl. Acad. Sci. USA, 81:6851-6855, 1984; Morrison and Oi, Adv.Immunol., 44:65-92, 1988; Verhoeyen et al., Science, 239:1534-1536,1988; Padlan, Molec. Immun., 28:489-498, 1991; and Padlan, Molec.Immun., 31:169-217, 1994. Other examples of human engineering technologyinclude, but are not limited to Xoma technology disclosed in U.S. Pat.No. 5,766,886.

The terms “identical” or percent “identity,” in the context of two ormore nucleic acids or polypeptide sequences, refer to two or moresequences or subsequences that are the same. Two sequences are“substantially identical” if two sequences have a specified percentageof amino acid residues or nucleotides that are the same (i.e., 60%identity, optionally 65%, 70%, 75%, 80%, 85%, 90%, 95%, or 99% identityover a specified region, or, when not specified, over the entiresequence), when compared and aligned for maximum correspondence over acomparison window, or designated region as measured using one of thefollowing sequence comparison algorithms or by manual alignment andvisual inspection. Optionally, the identity exists over a region that isat least about 50 nucleotides (or 10 amino acids) in length, or morepreferably over a region that is 100 to 500 or 1000 or more nucleotides(or 20, 50, 200 or more amino acids) in length.

For sequence comparison, typically one sequence acts as a referencesequence, to which test sequences are compared. When using a sequencecomparison algorithm, test and reference sequences are entered into acomputer, subsequence coordinates are designated, if necessary, andsequence algorithm program parameters are designated. Default programparameters can be used, or alternative parameters can be designated. Thesequence comparison algorithm then calculates the percent sequenceidentities for the test sequences relative to the reference sequence,based on the program parameters.

A “comparison window”, as used herein, includes reference to a segmentof any one of the number of contiguous positions selected from the groupconsisting of from 20 to 600, usually about 50 to about 200, moreusually about 100 to about 150 in which a sequence may be compared to areference sequence of the same number of contiguous positions after thetwo sequences are optimally aligned. Methods of alignment of sequencesfor comparison are well known in the art. Optimal alignment of sequencesfor comparison can be conducted, e.g., by the local homology algorithmof Smith and Waterman (1970) Adv. Appl. Math. 2:482c, by the homologyalignment algorithm of Needleman and Wunsch, J. Mol. Biol. 48:443, 1970,by the search for similarity method of Pearson and Lipman, Proc. Nat'l.Acad. Sci. USA 85:2444, 1988, by computerized implementations of thesealgorithms (GAP, BESTFIT, FASTA, and TFASTA in the Wisconsin GeneticsSoftware Package, Genetics Computer Group, 575 Science Dr., Madison,Wis.), or by manual alignment and visual inspection (see, e.g., Brent etal., Current Protocols in Molecular Biology, John Wiley & Sons, Inc.(Ringbou ed., 2003)).

Two examples of algorithms that are suitable for determining percentsequence identity and sequence similarity are the BLAST and BLAST 2.0algorithms, which are described in Altschul et al., (1977) Nuc. AcidsRes. 25:3389-3402; and Altschul et al., (1990) J. Mol. Biol.215:403-410, respectively. Software for performing BLAST analyses ispublicly available through the National Center for BiotechnologyInformation. This algorithm involves first identifying high scoringsequence pairs (HSPs) by identifying short words of length W in thequery sequence, which either match or satisfy some positive-valuedthreshold score T when aligned with a word of the same length in adatabase sequence. T is referred to as the neighborhood word scorethreshold (Altschul et al., supra). These initial neighborhood word hitsact as seeds for initiating searches to find longer HSPs containingthem. The word hits are extended in both directions along each sequencefor as far as the cumulative alignment score can be increased.Cumulative scores are calculated using, for nucleotide sequences, theparameters M (reward score for a pair of matching residues; always >0)and N (penalty score for mismatching residues; always <0). For aminoacid sequences, a scoring matrix is used to calculate the cumulativescore. Extension of the word hits in each direction are halted when: thecumulative alignment score falls off by the quantity X from its maximumachieved value; the cumulative score goes to zero or below, due to theaccumulation of one or more negative-scoring residue alignments; or theend of either sequence is reached. The BLAST algorithm parameters W, T,and X determine the sensitivity and speed of the alignment. The BLASTNprogram (for nucleotide sequences) uses as defaults a wordlength (W) of11, an expectation (E) or 10, M=5, N=−4 and a comparison of bothstrands. For amino acid sequences, the BLASTP program uses as defaults awordlength of 3, and expectation (E) of 10, and the BLOSUM62 scoringmatrix (see Henikoff and Henikoff, Proc. Natl. Acad. Sci. USA 89:10915,1989) alignments (B) of 50, expectation (E) of 10, M=5, N=−4, and acomparison of both strands.

The BLAST algorithm also performs a statistical analysis of thesimilarity between two sequences (see, e.g., Karlin and Altschul, Proc.Natl. Acad. Sci. USA 90:5873-5787, 1993). One measure of similarityprovided by the BLAST algorithm is the smallest sum probability (P(N)),which provides an indication of the probability by which a match betweentwo nucleotide or amino acid sequences would occur by chance. Forexample, a nucleic acid is considered similar to a reference sequence ifthe smallest sum probability in a comparison of the test nucleic acid tothe reference nucleic acid is less than about 0.2, more preferably lessthan about 0.01, and most preferably less than about 0.001.

The percent identity between two amino acid sequences can also bedetermined using the algorithm of E. Meyers and W. Miller (Comput. Appl.Biosci., 4:11-17, 1988) which has been incorporated into the ALIGNprogram (version 2.0), using a PAM120 weight residue table, a gap lengthpenalty of 12 and a gap penalty of 4. In addition, the percent identitybetween two amino acid sequences can be determined using the Needlemanand Wunsch (J. Mol, Biol. 48:444-453, 1970) algorithm which has beenincorporated into the GAP program in the GCG software package (availableon the world wide web at gcg.com), using either a Blossom 62 matrix or aPAM250 matrix, and a gap weight of 16, 14, 12, 10, 8, 6, or 4 and alength weight of 1, 2, 3, 4, 5, or 6.

Other than percentage of sequence identity noted above, anotherindication that two nucleic acid sequences or polypeptides aresubstantially identical is that the polypeptide encoded by the firstnucleic acid is immunologically cross reactive with the antibodiesraised against the polypeptide encoded by the second nucleic acid, asdescribed below. Thus, a polypeptide is typically substantiallyidentical to a second polypeptide, for example, where the two peptidesdiffer only by conservative substitutions. Another indication that twonucleic acid sequences are substantially identical is that the twomolecules or their complements hybridize to each other under stringentconditions, as described below. Yet another indication that two nucleicacid sequences are substantially identical is that the same primers canbe used to amplify the sequence.

The term “isolated antibody” refers to an antibody that is substantiallyfree of other antibodies having different antigenic specificities (e.g.,an isolated antibody that specifically binds FXI and/or FXIa issubstantially free of antibodies that specifically bind antigens otherthan FXI and/or FXIa, or an isolated anti-idiotype antibody thatspecifically binds an anti-FXI/FXIa antibody is substantially free ofantibodies that specifically bind antigens other than the anti-FXI/FXIaantibody). An isolated antibody that specifically binds FXI and/or FXIamay, however, have cross-reactivity to other antigens. Moreover, anisolated antibody may be substantially free of other cellular materialand/or chemicals.

The term “isotype” refers to the antibody class (e.g., IgM, IgE, IgGsuch as IgG1 or IgG4) that is provided by the heavy chain constantregion genes. Isotype also includes modified versions of one of theseclasses, where modifications have been made to alter the Fc function,for example, to enhance or reduce effector functions or binding to Fcreceptors.

The term “kassoc” or “ka”, as used herein, is intended to refer to theassociation rate of a particular antibody-antigen interaction, whereasthe term “kdis” or “kd,” as used herein, is intended to refer to thedissociation rate of a particular antibody-antigen interaction. The term“KD”, as used herein, is intended to refer to the dissociation constant,which is obtained from the ratio of kd to ka (i.e. kd/ka) and isexpressed as a molar concentration (M). KD values for antibodies can bedetermined using methods well established in the art. Methods fordetermining the KD of an antibody include measuring surface plasmonresonance using a biosensor system such as a Biacore™ system, ormeasuring affinity in solution by solution equilibrium titration (SET).

The terms “monoclonal antibody” or “monoclonal antibody composition” asused herein refer to a preparation of antibody molecules of singlemolecular composition. A monoclonal antibody composition displays asingle binding specificity and affinity for a particular epitope.

The term “nucleic acid” is used herein interchangeably with the term“polynucleotide” and refers to deoxyribonucleotides or ribonucleotidesand polymers thereof in either single- or double-stranded form. The termencompasses nucleic acids containing known nucleotide analogs ormodified backbone residues or linkages, which are synthetic, naturallyoccurring, and non-naturally occurring, which have similar bindingproperties as the reference nucleic acid, and which are metabolized in amanner similar to the reference nucleotides. Examples of such analogsinclude, without limitation, phosphorothioates, phosphoramidates, methylphosphonates, chiral-methyl phosphonates, 2-O-methyl ribonucleotides,peptide-nucleic acids (PNAs).

Unless otherwise indicated, a particular nucleic acid sequence alsoimplicitly encompasses conservatively modified variants thereof (e.g.,degenerate codon substitutions) and complementary sequences, as well asthe sequence explicitly indicated. Specifically, as detailed below,degenerate codon substitutions may be achieved by generating sequencesin which the third position of one or more selected (or all) codons issubstituted with mixed-base and/or deoxyinosine residues (Batzer et al.,Nucleic Acid Res. 19:5081, 1991; Ohtsuka et al., J. Biol. Chem.260:2605-2608, 1985; and Rossolini et al., Mol. Cell. Probes 8:91-98,1994).

The term “operably linked” refers to a functional relationship betweentwo or more polynucleotide (e.g., DNA) segments. Typically, the termrefers to the functional relationship of a transcriptional regulatorysequence to a transcribed sequence. For example, a promoter or enhancersequence is operably linked to a coding sequence if it stimulates ormodulates the transcription of the coding sequence in an appropriatehost cell or other expression system. Generally, promotertranscriptional regulatory sequences that are operably linked to atranscribed sequence are physically contiguous to the transcribedsequence, i.e., they are cis-acting. However, some transcriptionalregulatory sequences, such as enhancers, need not be physicallycontiguous or located in close proximity to the coding sequences whosetranscription they enhance.

As used herein, the term, “optimized” means that a nucleotide sequencehas been altered to encode an amino acid sequence using codons that arepreferred in the production cell or organism, generally a eukaryoticcell, for example, a cell of Pichia, a Chinese Hamster Ovary cell (CHO)or a human cell. The optimized nucleotide sequence is engineered toretain completely or as much as possible the amino acid sequenceoriginally encoded by the starting nucleotide sequence, which is alsoknown as the “parental” sequence. The optimized sequences herein havebeen engineered to have codons that are preferred in mammalian cells.However, optimized expression of these sequences in other eukaryoticcells or prokaryotic cells is also envisioned herein. The amino acidsequences encoded by optimized nucleotide sequences are also referred toas optimized.

The terms “polypeptide” and “protein” are used interchangeably herein torefer to a polymer of amino acid residues. The terms apply to amino acidpolymers in which one or more amino acid residue is an artificialchemical mimetic of a corresponding naturally occurring amino acid, aswell as to naturally occurring amino acid polymers and non-naturallyoccurring amino acid polymer. Unless otherwise indicated, a particularpolypeptide sequence also implicitly encompasses conservatively modifiedvariants thereof.

The term “recombinant human antibody”, as used herein, includes allhuman antibodies that are prepared, expressed, created or isolated byrecombinant means, such as antibodies isolated from an animal (e.g., amouse) that is transgenic or transchromosomal for human immunoglobulingenes or a hybridoma prepared therefrom, antibodies isolated from a hostcell transformed to express the human antibody, e.g., from atransfectoma, antibodies isolated from a recombinant, combinatorialhuman antibody library, and antibodies prepared, expressed, created orisolated by any other means that involve splicing of all or a portion ofa human immunoglobulin gene, sequences to other DNA sequences. Suchrecombinant human antibodies have variable regions in which theframework and CDR regions are derived from human germline immunoglobulinsequences. In certain embodiments, however, such recombinant humanantibodies can be subjected to in vitro mutagenesis (or, when an animaltransgenic for human Ig sequences is used, in vivo somatic mutagenesis)and thus the amino acid sequences of the VH and VL regions of therecombinant antibodies are sequences that, while derived from andrelated to human germline VH and VL sequences, may not naturally existwithin the human antibody germline repertoire in vivo.

The term “recombinant host cell” (or simply “host cell”) refers to acell into which a recombinant expression vector has been introduced. Itshould be understood that such terms are intended to refer not only tothe particular subject cell but to the progeny of such a cell. Becausecertain modifications may occur in succeeding generations due to eithermutation or environmental influences, such progeny may not, in fact, beidentical to the parent cell, but are still included within the scope ofthe term “host cell” as used herein.

The term “subject” includes human and non-human animals. Non-humananimals include all vertebrates (e.g.: mammals and non-mammals) such as,non-human primates (e.g.: cynomolgus monkey), sheep, rabbit, dog, cow,chickens, amphibians, and reptiles. Except when noted, the terms“patient” or “subject” are used herein interchangeably. As used herein,the terms “cyno” or “cynomolgus” refer to the cynomolgus monkey (Macacafascicularis). In some specific aspects provided herein, a patient or asubject is a human.

As used herein, the term “treating” or “treatment” of any disease ordisorder (e.g., a thromboembolic disorder) refers in one embodiment, toameliorating the disease or disorder (i.e., slowing or arresting orreducing the development of the disease or at least one of the clinicalsymptoms thereof). In another embodiment “treating” or “treatment”refers to alleviating or ameliorating at least one physical parameterincluding those which may not be discernible by the patient. In yetanother embodiment, “treating” or “treatment” refers to modulating thedisease or disorder, either physically, (e.g., stabilization of adiscernible symptom), physiologically, (e.g., stabilization of aphysical parameter), or both. In yet another embodiment, “treating” or“treatment” refers to preventing or delaying the onset or development orprogression of the disease or disorder.

“Prevention” as it relates to indications described herein, including,e.g., a thromboembolic disorder, means any action that prevents or slowsa worsening in e.g., a thromboembolic disease parameters, as describedbelow, in a patient at risk for being afflicted with a thromboembolicdisorder or at risk for said worsening.

The term “vector” is intended to refer to a polynucleotide moleculecapable of transporting another polynucleotide to which it has beenlinked. One type of vector is a “plasmid”, which refers to a circulardouble stranded DNA loop into which additional DNA segments may beligated. Another type of vector is a viral vector, such as anadeno-associated viral vector (AAV, or AAV2), wherein additional DNAsegments may be ligated into the viral genome. Certain vectors arecapable of autonomous replication in a host cell into which they areintroduced (e.g., bacterial vectors having a bacterial origin ofreplication and episomal mammalian vectors). Other vectors (e.g.,non-episomal mammalian vectors) can be integrated into the genome of ahost cell upon introduction into the host cell, and thereby arereplicated along with the host genome. Moreover, certain vectors arecapable of directing the expression of genes to which they areoperatively linked. Such vectors are referred to herein as “recombinantexpression vectors” (or simply, “expression vectors”). In general,expression vectors of utility in recombinant DNA techniques are often inthe form of plasmids. In the present specification, “plasmid” and“vector” may be used interchangeably as the plasmid is the most commonlyused form of vector. However, the present disclosure is intended toinclude such other forms of expression vectors, such as viral vectors(e.g., replication defective retroviruses, adenoviruses andadeno-associated viruses), which serve equivalent functions.

Factor XI/XIa and Anti-Factor XI/FXIa Antibodies

This section describes exemplary anti-FXI/FXIa antibodies (e.g.,antibodies described in Table 1) to which reversal binding agentsprovided herein (e.g., anti-idiotype antibodies and fragments thereof)specifically bind, wherein reversal binding agents are capable ofreversing one or more anticoagulant effects of such anti-FXI/FXIaantibodies and/or inhibits binding of such anti-FXI/FXIa antibodies toFXI and/or FXIa.

FXI holds important roles in both intrinsic and extrinsic coagulationpathways and in bridging the initiation and amplification phases ofplasmatic hemostasis. Both Factor XIIa and thrombin can activate FXI,resulting in a sustained thrombin generation and fibrinolysisinhibition. FXI plays a minor role in normal hemostasis in a high tissuefactor environment “after vessel injury” whereas it appears to play akey role in thrombosis. Severe Factor XI deficiency is associated with alower incidence of ischemic stroke and venous thromboembolic events(Salomon et al 2008; Salomon, et al. (2011) Thromb Haemost.;105:269-73). Bleeding manifestations in subjects with severe factor XIdeficiency are infrequent, often mild, injury-induced and affectpreferably tissues with increased fibrinolytic activity such as the oralmucosa, nasal mucosa and urinary tract (Salomon et al 2011). Bleeding incritical organs is extremely rare or not existing.

Plasma coagulation is a sequential process by which coagulation factorsin the blood interact and are activated, ultimately resulting in fibringeneration and clot formation. In the classical cascade model ofcoagulation, the process of fibrin generation can be initiated by twodistinct pathways, i.e., the intrinsic and the extrinsic pathway,respectively (Mackman, 2008).

In the extrinsic pathway, vessel injury allows extravascular tissuefactor (TF) to interact with and activate factor VII (FVII), whichsequentially leads to the activation of factor X and prothrombin. Theactive thrombin ultimately converts soluble fibrinogen into fibrin. Theextrinsic pathway is central for hemostasis, interfering withcoagulation factors in this pathway results in a risk of bleeding.

In the intrinsic pathway, factor XII may in some cases be activated by aprocess referred to as contact activation. Generation of activatedfactor XIIa leads to the sequential activations of factor XI and factorIX. As factor IXa activates factor X, the extrinsic and intrinsicpathways converge at this stage (at the common pathway). Thrombinactivity is boosted by amplifying its own generation through afeed-forward loop in which thrombin activates factor XI independently offactor XII. This feed-forward loop contributes to sustained thrombusgrowth but is only minimally involved in hemostasis, as the strongactivation by extravascular tissue factor is sufficient to clotformation. The intrinsic pathway therefore is not substantially involvedin hemostasis (Gailani and Renne (2007) Arterioscler Thromb Vasc Biol.2007, 27(12):2507-13, Muller Gailiani, and Renne 2011).

Preclinical studies using a variety of approaches to inhibit FXI or FXIaacross a variety of species have contributed to the validation of thistarget. FXI−/− mice are resistant to experimental venous (Wang, et al.(2006) J Thromb Haemost; 4:1982-8) and arterial (Wang, et al. (2005) JThromb Haemost; 3:695-702) thrombosis. Treatment of mice with anantibody (Ab, 14E11) that blocks the activation of FXI by FXIIa resultedin inhibition of experimental thrombosis (Cheng, et al. (2010) Blood,116:3981-9) and reduced cerebral infarct size in a mouse model ofischemic stroke (Leung, et al. (2012) Transl Stroke Res 2012; 3:381-9).In baboons administered an anti-FXI antibody that blocks binding andactivation of FIX by FXIa, reduced growth of platelet-rich thrombi wasobserved on collagen-coated vascular grafts (Tucker, et al. (2009) Blood2009; 113:936-44), and similar results were found with 14E11 in thismodel (Cheng 2010). Excessive bleeding was not noted in any of thesestudies.

Blocking FXI synthesis with antisense oligonucleotides in mice (Zhang,et al. (2010) Blood 2010; 116:4684-92), cynomolgus monkeys (Younis, etal. (2012) Blood 2012; 119:2401-8), and baboons (Crosby, et al. (2013)Arterioscler Thromb Vasc Biol 2013; 33:1670-8) resulted inantithrombotic and anticoagulant effects without excessive bleeding.Moreover, similar effects have been produced by blocking FXIa with lowmolecular weight inhibitors in venous and arterial models of thrombosisin rats (Schumacher, et al. (2007) Eur J Pharmacol 2007; 570:167-74) andrabbits (Wong, et al. (2011) J Thromb Thrombolysis 2011; 32:129-37).

Patients with severe FXI deficiency rarely bleed spontaneously and theyshow only mild trauma-induced bleeding, except in tissues with highfibrinolytic activity. The rarity of severe FXI deficiency necessitatesthe use of population studies for revealing the thrombotic profile ofthese patients relative to the general population. Notably, such studiesreport the incidence of ischemic stroke (Salomon 2008) and deep veinthrombosis (DVT) (Salomon, et al. (2011) Blood 2008; 111: 4113-17) to bereduced in these patients. Thus, the number of ischemic strokes (N=1)observed in 115 patients with severe FXI deficiency was less (p<0.003)than the expected incidence (N=8.6) in the general population of Israel,while the incidence of DVT (N=0) was lower (p<0.019) in patients withsevere FXI deficiency than expected in the control population (N=4.7).Conversely, individuals with FXI levels above the 90th percentile had atwo-fold risk of developing DVT (Meijers, et al. (2000) N Engl J Med.2000; 342:696-701).

Recently, patients undergoing total knee replacement, a procedure thatpredisposes to DVT, were treated with FXI antisense therapy or standardof care (enoxaparin). The antisense group (300 mg) showed a 7-folddecreased incidence in venous thrombosis and fewer (not significant)bleeding events compared to standard of care (Buller et al, (2014) NEngl J Med. 372(3):232-40. doi: 10.1056/NEJMoa1405760. Epub 2014 Dec.7).

Antibodies that specifically bind to FXI and/or FXIa have beendescribed. See for example, PCT International Publication Nos.WO2017/015619, WO2016/207858, WO 2013/167669, WO2009/067660, WO2009/154461, and WO 2010/080623, each of which is incorporated byreference herein in its entirety. Non-limiting examples of anti-FXI/FXIaantibodies include: 076D-M007-H04, 076D-M007-H04-CDRL3-N110D, and076D-M028-H17 as described in WO 2013/167669; 1A6 as described inWO2009/067660; and 14E11 as described in WO 2010/080623. In specificaspects, provided herein are binding agents, such as anti-idiotypeantibodies, that specifically bind to anti-FXI/FXIa antibody076D-M007-H04, 076D-M007-H04-CDRL3-N110D, or 076D-M028-H17, and iscapable of inhibiting binding of the anti-FXI/FXIa antibody to FXI/FXIaand/or is capable of reversing an anticoagulant effect of theanti-FXI/FXIa antibody. In specific aspects, provided herein are bindingagents, such as anti-idiotype antibodies that specifically bind to ananti-FXI/FXIa antibody which competes (e.g., in a dose-dependent manner)with 076D-M007-H04, 076D-M007-H04-CDRL3-N110D, or 076D-M028-H17 forbinding to FXI/FXIa, and is capable of inhibiting binding of theanti-FXI/FXIa antibody to FXI/FXIa and/or is capable of reversing ananticoagulant effect of the anti-FXI/FXIa antibody.

Table 1 provides exemplary amino acid sequences and correspondingencoding nucleotide sequences for human FXI and anti-FXI/FXIaantibodies, for example, antibody NOV1401 and NOV1090. In particular,Table 1 provides the following amino acid sequences for antibodiesNOV1401, NOV1090, AM1, AM2, AM3, and AM4, as well as correspondingencoding nucleotide sequences: heavy chain variable region (VH), lightchain variable region (VL), heavy chain, light chain, VH complementaritydetermining regions HCDR1, HCDR2, and HCDR3, VL complementaritydetermining regions LCDR1, LCDR2, and LCDR3. In specific aspects,reversal binding agents provided herein specifically bind to ananti-FXI/FXIa antibody described in Table 1 and is capable of inhibiting(e.g., in a dose dependent manner) binding of the anti-FXI/FXIa antibodyto human FXI/FXIa, and/or of reversing one or more anticoagulantactivities of the anti-FXI/FXIa antibody. In specific aspects, reversalbinding agents provided herein (e.g., anti-idiotype antibody orantigen-binding fragment thereof such a Fab) specifically bind toanti-FXI/FXIa antibody NOV1401, NOV1090, AM1, AM2, AM3, and/or AM4, andis capable of inhibiting binding of the anti-FXI/FXIa antibody to humanFXI/FXIa and/or is capable of reversing an anticoagulant effect of theanti-FXI/FXIa antibody.

Antibody NOV1401 is a human antibody which specifically binds thecatalytic domain of human FXI, and has been previously described, see,for example, PCT International Patent Application No. PCT/IB2016/053790filed on Jun. 24, 2016 (PCT International Publication No. WO2016/207858)and U.S. patent application Ser. No. 15/192,020 filed on Jun. 24, 2016,each of which is hereby incorporated by reference in its entirety.Antibody NOV1401 is capable of binding both human FXI zymogen as well asFXIa. NOV1401 has been described to contact human FXI/FXIa epitopesformed of the following residues: Pro410, Arg413, Leu415, Cys416,His431, Cys432, Tyr434, Gly435, Glu437, Tyr472, Lys473, Met474, Ala475,Glu476, Tyr521, Arg522, Lys523, Leu524, Arg525, Asp526, Lys527, Arg548,His552, Ser575, Ser594, Trp595, Gly596, Glu597, Arg602, Glu603, andArg604 (see PCT International Publication No. WO2016/207858). Inspecific aspects, antibody NOV1401 contacts one, two, three, four, five,six, seven, eight, nine, ten, eleven, twelve, thirteen, fourteen,fifteen or more, or all of, amino acid residues of human FXI selectedfrom: Pro410, Arg413, Leu415, Cys416, His431, Cys432, Tyr434, Gly435,Glu437, Tyr472, Lys473, Met474, Ala475, Glu476, Tyr521, Arg522, Lys523,Leu524, Arg525, Asp526, Lys527, Arg548, His552, Ser575, Ser594, Trp595,Gly596, Glu597, Arg602, Glu603, and Arg604.

In addition, the paratope of NOV1401 has been described (see PCTInternational Publication No. WO2016/207858). In particular, thefollowing residues of the light chain of NOV1401 contact human FXI/FXIa:Ser27, Gly30, Ser31, Asn32, Asp33, Tyr50, Lys51, Tyr53, Asn54, Lys67,Trp92, Gln94, Arg95, Phe97, Asp98, and Val99 (residues are numbered withreference to SEQ ID NO: 25); and the following residues of the heavychain of NOV1401 contact human FXI/FXIa: Phe27, Thr28, Ser30, Thr31,Ala33, Trp47, Ser52, Tyr59, Tyr60, Glu99, Ser101, Tyr102, Leu103,Tyr104, and Ser105 (residues are numbered with reference to SEQ ID NO:14). Accordingly, in specific aspects, provided herein are reversalbinding agents (e.g., anti-idiotype antibodies and fragment thereof suchas Fabs) that bind to the antigen-binding region of NOV1401, andcontacts one or more of the residues in light chain and heavy chain ofNOV1401 forming the paratope. In specific aspects, a reversal bindingagent agent (e.g., anti-idiotype antibody and fragment thereof such as aFab) provided herein binds to NOV1401 within the antigen-binding region,and contacts one, two, three, four, five six, seven, eight, nine, ormore, or all, of the following residues in the light chain of NOV1401:Ser27, Gly30, Ser31, Asn32, Asp33, Tyr50, Lys51, Tyr53, Asn54, Lys67,Trp92, Gln94, Arg95, Phe97, Asp98, and Val99 (residues are numbered withreference to SEQ ID NO: 25). In specific aspects, a reversal bindingagent agent (e.g., anti-idiotype antibody and fragment thereof such as aFab) provided herein binds to NOV1401 within the antigen-binding region,and contacts one, two, three, four, five six, seven, eight, nine, ormore, or all, of the following residues in the heavy chain of NOV1401contact human FXI/FXIa: Phe27, Thr28, Ser30, Thr31, Ala33, Trp47, Ser52,Tyr59, Tyr60, Glu99, Ser101, Tyr102, Leu103, Tyr104, and Ser105(residues are numbered with reference to SEQ ID NO: 14). In specificaspects, a reversal binding agent agent (e.g., anti-idiotype antibodyand fragment thereof such as a Fab) provided herein binds to NOV1401within the antigen-binding region, and contacts one, two, three, four,five six, seven, eight, nine, ten or more amino acid residues selectedfrom the following in light chain and/or the heavy chain of NOV1401forming the paratope: (i) Ser27, Gly30, Ser31, Asn32, Asp33, Tyr50,Lys51, Tyr53, Asn54, Lys67, Trp92, Gln94, Arg95, Phe97, Asp98, and Val99in the light chain of NOV1401 (residues are numbered with reference toSEQ ID NO: 25); and (ii) Phe27, Thr28, Ser30, Thr31, Ala33, Trp47,Ser52, Tyr59, Tyr60, Glu99, Ser101, Tyr102, Leu103, Tyr104, and Ser105in the heavy chain of NOV1401 (residues are numbered with reference toSEQ ID NO: 14).

Other anti-FXI/FXIa antibodies described in Table 1 herein includeNOV1090, AM1, AM2, AM3, and AM4. Antibodies NOV1401 and NOV1090 sharethe same CDRs. Antibodies AM1, AM2, AM3, and AM4 are exemplary affinitymatured variants of antibody NOV1090.

In specific aspects, reversal binding agents provided herein (e.g.,anti-idiotype antibodies) bind to an anti-FXI/FXIa antibody whichcompetes (e.g., in a dose dependent manner) with NOV1401 for binding tohuman FXI/FXIa. In other aspects, reversal binding agents providedherein (e.g., human anti-idiotype antibodies) bind to an anti-FXI/FXIaantibody which binds to the same epitope of FXI/FXIa as NOV1401. Inparticular aspects, reversal binding agents provided herein (e.g., humananti-idiotype antibodies) bind to an anti-FXI/FXIa antibody whichcontacts one, two, three, four, five, six, seven, eight, nine, ten,eleven, twelve, thirteen, fourteen, fifteen or more, or all of, aminoacid residues of human FXI selected from: Pro410, Arg413, Leu415,Cys416, His431, Cys432, Tyr434, Gly435, Glu437, Tyr472, Lys473, Met474,Ala475, Glu476, Tyr521, Arg522, Lys523, Leu524, Arg525, Asp526, Lys527,Arg548, His552, Ser575, Ser594, Trp595, Gly596, Glu597, Arg602, Glu603,and Arg604. In specific aspects, reversal binding agents provided herein(e.g., human anti-idiotype antibodies) bind to an anti-FXI/FXIa antibodywhich is NOV1401 or competes for binding with NOV1401 to human FXI/FXIaand which anti-FXI/FXIa antibody does not contact amino acid residueAsp480 of human FXI/FXIa. In specific aspects, reversal binding agentsprovided herein (e.g., human anti-idiotype antibodies) bind to ananti-FXI/FXIa antibody which is NOV1401 or competes for binding withNOV1401 to human FXI/FXIa and which anti-FXI/FXIa antibody does notcontact one or more amino acid residues selected from: His414, Ser477,Asp480, Lys572, Asp569, and Gly598 of human FXI/FXIa. In specificaspects, reversal binding agents provided herein (e.g., humananti-idiotype antibodies) bind to an anti-FXI/FXIa antibody which isNOV1401 or competes for binding with NOV1401 to human FXI/FXIa and whichanti-FXI/FXIa antibody contacts one, two, three, four, five, six, seven,eight, or more, or all, of amino acid residues Leu415, Cys416, His431,Cys432, Gly435, Glu437, Tyr472, Lys473, Glu476, Arg548, His552, Ser575,Trp595, Gly596, Glu597, Arg602, Glu603, and Arg604 of human FXI/FXIa. Inspecific aspects, reversal binding agents provided herein (e.g., humananti-idiotype antibodies) bind to an anti-FXI/FXIa antibody whichcontacts amino acid residues His431 and Ser575 of human FXI/FXIa.

In particular aspects, an anti-FXI/FXIa antibody has one or more of thefollowing anticoagulant activities, which can be reversed (e.g.,partially reversed) by a reversal binding agent (e.g., anti-idiotypeantibody or fragment thereof such as Fab) provided herein: (i) aPTTprolongation as determined by aPTT assay, (ii) reduction in the amountof thrombin in a thrombin generation assay (TGA) in human plasma, and(iii) inhibition of Factor XI activity. These activities can be readilymeasured with assays described in the art and provided herein. Forexample, TGA and aPTT assays are described in the art and herein (e.g.,Examples Section). In further aspects, other biomarkers of the extrinsiccoagulation pathway can be measured to determine anticoagulant activity,for example, prothrombin time (PT) assay and thrombin time (TT) assay.Other, non-limiting examples of assays for anticoagulation/coagulationactivity include chromogenic assays such as ecarin chromogenic assay(ECA), ecarin clotting time (ECT) assay, and anti-Factor Xa activityassay. In specific aspects, reversal binding agents provided herein(e.g., anti-idiotype antibodies) is capable of reversing (e.g.,partially reversing) one or more of these anticoagulant activities. Inparticular aspects, reversal binding agents provided herein is capableof reducing the bleeding time in patients administered an anti-FXI/FXIaantibody.

TABLE 1 Examples of FXI/FXIa Antibodies, Fabs and FXI/FXIa ProteinsSequence Description Identifier Amino acid or polynucleotide sequenceHuman FXI full-   1 MIFLYQVVHF ILFTSVSGEC VTQLLKDTCF EGGDITTVFTlength protein PSAKYCQVVC TYHPRCLLFT FTAESPSEDP TRWFTCVLKDsequence (NCBI SVTETLPRVN RTAAISGYSF KQCSHQISAC NKDIYVDLDM ReferenceKGINYNSSVA KSAQECQERC TDDVHCHFFT YATRQFPSLE Sequence:HRNICLLKHT QTGTPTRITK LDKVVSGFSL KSCALSNLAC AAA51985)IRDIFPNTVF ADSNIDSVMA PDAFVSGRIC THHPGCLFFTFFSQEWPKES QRNLCLLKTS ESGLPSTRIK KSKALSGFSLQSCRHSIPVF CHSSFYHDTD FLGEELDIVA AKSHEACQKLCTNAVRCQFF TYTPAQASCN EGKGKCYLKL SSNGSPTKILHGRGGISGYT LRLCKMDNEC TTKIKPRIVG GTASVRGEWPWQVTLHTTSP TQRHLCGGSI IGNQWILTAA HCFYGVESPKILRVYSGILN QSEIKEDTSF FGVQEIIIHD QYKMAESGYDIALLKLETTV NYTDSQRPIC LPSKGDRNVI YTDCWVTGWGYRKLRDKIQN TLQKAKIPLV TNEECQKRYR GHKITHKMICAGYREGGKDA CKGDSGGPLS CKHNEVWHLV GITSWGEGCA QRERPGVYTN VVEYVDWILE KTQAVHuman FXI full-   2 AGGCACACAG GCAAAATCAA GTTCTACATC TGTCCCTGTG lengthTATGTCACTT GTTTGAATAC GAAATAAAAT TAAAAAAATA nucleotideAATTCAGTGT ATTGAGAAAG CAAGCAATTC TCTCAAGGTA sequence (NCBITATTTCTGAC ATACTAAGAT TTTAACGACT TTCACAAATA ReferenceTGCTGTACTG AGAGAGAATG TTACATAACA TTGAGAACTA Sequence:GTACAAGTAA ATATTAAAGT GAAGTGACCA TTTCCTACAC NM_000128.3)AAGCTCATTC AGAGGAGGAT GAAGACCATT TTGGAGGAAGAAAAGCACCC TTATTAAGAA TTGCAGCAAG TAAGCCAACAAGGTCTTTTC AGGATGATTT TCTTATATCA AGTGGTACATTTCATTTTAT TTACTTCAGT TTCTGGTGAA TGTGTGACTCAGTTGTTGAA GGACACCTGC TTTGAAGGAG GGGACATTACTACGGTCTTC ACACCAAGCG CCAAGTACTG CCAGGTAGTCTGCACTTACC ACCCAAGATG TTTACTCTTC ACTTTCACGGCGGAATCACC ATCTGAGGAT CCCACCCGAT GGTTTACTTGTGTCCTGAAA GACAGTGTTA CAGAAACACT GCCAAGAGTGAATAGGACAG CAGCGATTTC TGGGTATTCT TTCAAGCAATGCTCACACCA AATAAGCGCT TGCAACAAAG ACATTTATGTGGACCTAGAC ATGAAGGGCA TAAACTATAA CAGCTCAGTTGCCAAGAGTG CTCAAGAATG CCAAGAAAGA TGCACGGATGACGTCCACTG CCACTTTTTC ACGTACGCCA CAAGGCAGTTTCCCAGCCTG GAGCATCGTA ACATTTGTCT ACTGAAGCACACCCAAACAG GGACACCAAC CAGAATAACG AAGCTCGATAAAGTGGTGTC TGGATTTTCA CTGAAATCCT GTGCACTTTCTAATCTGGCT TGTATTAGGG ACATTTTCCC TAATACGGTGTTTGCAGACA GCAACATCGA CAGTGTCATG GCTCCCGATGCTTTTGTCTG TGGCCGAATC TGCACTCATC ATCCCGGTTGCTTGTTTTTT ACCTTCTTTT CCCAGGAATG GCCCAAAGAATCTCAAAGAA ATCTTTGTCT CCTTAAAACA TCTGAGAGTGGATTGCCCAG TACACGCATT AAAAAGAGCA AAGCTCTTTCTGGTTTCAGT CTACAAAGCT GCAGGCACAG CATCCCAGTGTTCTGCCATT CTTCATTTTA CCATGACACT GATTTCTTGGGAGAAGAACT GGATATTGTT GCTGCAAAAA GTCACGAGGCCTGCCAGAAA CTGTGCACCA ATGCCGTCCG CTGCCAGTTTTTTACCTATA CCCCAGCCCA AGCATCCTGC AACGAAGGGAAGGGCAAGTG TTACTTAAAG CTTTCTTCAA ACGGATCTCCAACTAAAATA CTTCACGGGA GAGGAGGCAT CTCTGGATACACATTAAGGT TGTGTAAAAT GGATAATGAG TGTACCACCAAAATCAAGCC CAGGATCGTT GGAGGAACTG CGTCTGTTCGTGGTGAGTGG CCGTGGCAGG TGACCCTGCA CACAACCTCACCCACTCAGA GACACCTGTG TGGAGGCTCC ATCATTGGAAACCAGTGGAT ATTAACAGCC GCTCACTGTT TCTATGGGGTAGAGTCACCT AAGATTTTGC GTGTCTACAG TGGCATTTTAAATCAATCTG AAATAAAAGA GGACACATCT TTCTTTGGGGTTCAAGAAAT AATAATCCAT GATCAGTATA AAATGGCAGAAAGCGGGTAT GATATTGCCT TGTTGAAACT GGAAACCACAGTGAATTACA CAGATTCTCA ACGACCCATA TGCCTGCCTTCCAAAGGAGA TAGAAATGTA ATATACACTG ATTGCTGGGTGACTGGATGG GGGTACAGAA AACTAAGAGA CAAAATACAAAATACTCTCC AGAAAGCCAA GATACCCTTA GTGACCAACGAAGAGTGCCA GAAGAGATAC AGAGGACATA AAATAACCCATAAGATGATC TGTGCCGGCT ACAGGGAAGG AGGGAAGGACGCTTGCAAGG GAGATTCGGG AGGCCCTCTG TCCTGCAAACACAATGAGGT CTGGCATCTG GTAGGCATCA CGAGCTGGGGCGAAGGCTGT GCTCAAAGGG AGCGGCCAGG TGTTTACACCAACGTGGTCG AGTACGTGGA CTGGATTCTG GAGAAAACTCAAGCAGTGTG AATGGGTTCC CAGGGGCCAT TGGAGTCCCTGAAGGACCCA GGATTTGCTG GGAGAGGGTG TTGAGTTCACTGTGCCAGCA TGCTTCCTCC ACAGTAACAC GCTGAAGGGGCTTGGTGTTT GTAAGAAAAT GCTAGAAGAA AACAAACTGTCACAAGTTGT TATGTCCAAA ACTCCCGTTC TATGATCGTTGTAGTTTGTT TGAGCATTCA GTCTCTTTGT TTTTGATCACGCTTCTATGG AGTCCAAGAA TTACCATAAG GCAATATTTCTGAAGATTAC TATATAGGCA GATATAGCAG AAAATAACCAAGTAGTGGCA GTGGGGATCA GGCAGAAGAA CTGGTAAAAGAAGCCACCAT AAATAGATTT GTTCGATGAA AGATGAAAACTGGAAGAAAG GAGAACAAAG ACAGTCTTCA CCATTTTGCAGGAATCTACA CTCTGCCTAT GTGAACACAT TTCTTTTGTAAAGAAAGAAA TTGATTGCAT TTAATGGCAG ATTTTCAGAATAGTCAGGAA TTCTTGTCAT TTCCATTTTA AAATATATATTAAAAAAAAT CAGTTCGAGT AGACACGAGC TAAGAGTGAATGTGAAGATA ACAGAATTTC TGTGTGGAAG AGGATTACAAGCAGCAATTT ACCTGGAAGT GATACCTTAG GGGCAATCTTGAAGATACAC TTTCCTGAAA AATGATTTGT GATGGATTGTATATTTATTT AAAATATCTT GGGAGGGGAG GCTGATGGAGATAGGGAGCA TGCTCAAACC TCCCTAAGAC AAGCTGCTGCTGTGACTATG GGCTCCCAAA GAGCTAGATC GTATATTTATTTGACAAAAA TCACCATAGA CTGCATCCAT ACTACAGAGAAAAAACAATT AGGGCGCAAA TGGATAGTTA CAGTAAAGTCTTCAGCAAGC AGCTGCCTGT ATTCTAAGCA CTGGGATTTTCTGTTTCGTG CAAATATTTA TCTCATTATT GTTGTGATCTAGTTCAATAA CCTAGAATTT GAATTGTCAC CACATAGCTTTCAATCTGTG CCAACAACTA TACAATTCAT CAAGTGTG NOV1401 HCDR1   3 GFTFSTAAMS(Combined) HCDR2   4 GISGSGSSTYYADSVKG (Combined) HCDR3   5ELSYLYSGYYFDY (Combined) HCDR1 (Kabat)   6 TAAMS HCDR2 (Kabat)   4GISGSGSSTYYADSVKG HCDR3 (Kabat)   5 ELSYLYSGYYFDY HCDR1   7 GFTFSTA(Chothia) HCDR2   8 SGSGSS (Chothia) HCDR3   5 ELSYLYSGYYFDY (Chothia)HCDR1 (IMGT)   9 GFTFSTAA HCDR2 (IMGT)  10 ISGSGSST HCDR3 (IMGT)  11ARELSYLYSGYYFDY VH  12 QVQLLESGGGLVQPGGSLRLSCAASGFTFSTAAMSWVRQAPGKGLEWVSGISGSGSSTYYADSVKGRFTISRDNSKNTLYLQMNSLRAEDTAVYYCARELSYLYSGYYFDYWGQGTLVTVSS DNA encoding VH  13CAGGTGCAGCTGCTGGAATCAGGCGGCGGACTGGTGCAGCCTGGCGGTAGCCTGAGACTGAGCTGCGCTGCTAGTGGCTTCACCTTTAGCACCGCCGCTATGAGCTGGGTTCGACAGGCCCCAGGGAAAGGCCTCGAGTGGGTCTCAGGGATTAGCGGTAGCGGCTCTAGCACCTACTACGCCGATAGCGTGAAGGGCCGGTTCACTATCTCTAGGGATAACTCTAAGAACACCCTGTACCTGCAGATGAATAGCCTGAGAGCCGAGGACACCGCCGTCTACTACTGCGCTAGAGAGCTGAGCTACCTGTATAGCGGCTACTACTTCGACTACTGGGGTCAAGG CACCCTGGTCACCGTGTCTAGCHeavy Chain  14 QVQLLESGGGLVQPGGSLRLSCAASGFTFSTAAMSWVRQAPGKGLEWVSGISGSGSSTYYADSVKGRFTISRDNSKNTLYLQMNSLRAEDTAVYYCARELSYLYSGYYFDYWGQGTLVTVSSASTKGPSVFPLAPSSKSTSGGTAALGCLVKDYFPEPVTVSWNSGALTSGVHTFPAVLQSSGLYSLSSVVTVPSSSLGTQTYICNVNHKPSNTKVDKRVEPKSCDKTHTCPPCPAPELLGGPSVFLFPPKPKDTLMISRTPEVTCVVVAVSHEDPEVKFNWYVDGVEVHNAKTKPREEQYNSTYRVVSVLTVLHQDWLNGKEYKCKVSNKALAAPIEKTISKAKGQPREPQVYTLPPSREEMTKNQVSLTCLVKGFYPSDIAVEWESNGQPENNYKTTPPVLDSDGSFFLYSKLTVDKSRWQQGNVFSC SVMHEALHNHYTQKSLSLSPGKDNA encoding  15 CAGGTGCAGCTGCTGGAATCAGGCGGCGGACTGGTGCAGCCTG Heavy ChainGCGGTAGCCTGAGACTGAGCTGCGCTGCTAGTGGCTTCACCTTTAGCACCGCCGCTATGAGCTGGGTTCGACAGGCCCCAGGGAAAGGCCTCGAGTGGGTCTCAGGGATTAGCGGTAGCGGCTCTAGCACCTACTACGCCGATAGCGTGAAGGGCCGGTTCACTATCTCTAGGGATAACTCTAAGAACACCCTGTACCTGCAGATGAATAGCCTGAGAGCCGAGGACACCGCCGTCTACTACTGCGCTAGAGAGCTGAGCTACCTGTATAGCGGCTACTACTTCGACTACTGGGGTCAAGGCACCCTGGTCACCGTGTCTAGCGCTAGCACTAAGGGCCCCTCCGTGTTCCCTCTGGCCCCTTCCAGCAAGTCTACCTCCGGCGGCACAGCTGCTCTGGGCTGCCTGGTCAAGGACTACTTCCCTGAGCCTGTGACAGTGTCCTGGAACTCTGGCGCCCTGACCTCTGGCGTGCACACCTTCCCTGCCGTGCTGCAGTCCTCCGGCCTGTACTCCCTGTCCTCCGTGGTCACAGTGCCTTCAAGCAGCCTGGGCACCCAGACCTATATCTGCAACGTGAACCACAAGCCTTCCAACACCAAGGTGGACAAGCGGGTGGAGCCTAAGTCCTGCGACAAGACCCACACCTGTCCTCCCTGCCCTGCTCCTGAACTGCTGGGCGGCCCTTCTGTGTTCCTGTTCCCTCCAAAGCCCAAGGACACCCTGATGATCTCCCGGACCCCTGAAGTGACCTGCGTGGTGGTGGCCGTGTCCCACGAGGATCCTGAAGTGAAGTTCAATTGGTACGTGGACGGCGTGGAGGTGCACAACGCCAAGACCAAGCCTCGGGAGGAACAGTACAACTCCACCTACCGGGTGGTGTCCGTGCTGACCGTGCTGCACCAGGACTGGCTGAACGGCAAAGAGTACAAGTGCAAAGTCTCCAACAAGGCCCTGGCCGCCCCTATCGAAAAGACAATCTCCAAGGCCAAGGGCCAGCCTAGGGAACCCCAGGTGTACACCCTGCCACCCAGCCGGGAGGAAATGACCAAGAACCAGGTGTCCCTGACCTGTCTGGTCAAGGGCTTCTACCCTTCCGATATCGCCGTGGAGTGGGAGTCTAACGGCCAGCCTGAGAACAACTACAAGACCACCCCTCCTGTGCTGGACTCCGACGGCTCCTTCTTCCTGTACTCCAAACTGACCGTGGACAAGTCCCGGTGGCAGCAGGGCAACGTGTTCTCCTGCTCCGTGATGCACGAGGCCCTGCACAACCACTACACCCAGAAGT CCCTGTCCCTGTCTCCCGGCAAGLCDR1  16 SGSSSNIGSNDVS (Combined) LCDR2  17 KNYNRPS (Combined) LCDR3 18 SAWDQRQFDVV (Combined) LCDR1 (Kabat)  16 SGSSSNIGSNDVS LCDR2 (Kabat) 17 KNYNRPS LCDR3 (Kabat)  18 SAWDQRQFDVV LCDR1  19 SSSNIGSND (Chothia)LCDR2  20 KNY (Chothia) LCDR3  21 WDQRQFDV (Chothia) LCDR1 (IMGT)  22SSNIGSND LCDR2 (IMGT)  20 KNY LCDR3 (IMGT)  18 SAWDQRQFDVV VL  23QSVLTQPPSASGTPGQRVTISCSGSSSNIGSNDVSWYQQLPGTAPKLLIYKNYNRPSGVPDRFSGSKSGTSASLAISGLQSEDEAD YYCSAWDQRQFDVVFGGGTKLTVLDNA encoding VL  24 CAGTCAGTCCTGACTCAGCCCCCTAGCGCTAGTGGCACCCCTGGTCAAAGAGTGACTATTAGCTGTAGCGGCTCTAGCTCTAATATCGGCTCTAACGACGTCAGCTGGTATCAGCAGCTGCCCGGCACCGCCCCTAAGCTGCTGATCTATAAGAACTATAATAGGCCTAGCGGCGTGCCCGATAGGTTTAGCGGATCTAAATCAGGGACTTCTGCTAGTCTGGCTATTAGCGGCCTGCAGTCAGAGGACGAGGCCGACTACTACTGTAGCGCCTGGGATCAGCGTCAGTTCGACGTGGTGTTCGGCGGAGGCACTAAGCTGACCGTGCTG Light Chain  25QSVLTQPPSASGTPGQRVTISCSGSSSNIGSNDVSWYQQLPGTAPKLLIYKNYNRPSGVPDRFSGSKSGTSASLAISGLQSEDEADYYCSAWDQRQFDVVFGGGTKLTVLGQPKAAPSVTLFPPSSEELQANKATLVCLISDFYPGAVTVAWKADSSPVKAGVETTTPSKQSNNKYAASSYLSLTPEQWKSHRSYSCQVTHEGSTVEKTVAPTEC S DNA encoding  26CAGTCAGTCCTGACTCAGCCCCCTAGCGCTAGTGGCACCCCTG Light ChainGTCAAAGAGTGACTATTAGCTGTAGCGGCTCTAGCTCTAATATCGGCTCTAACGACGTCAGCTGGTATCAGCAGCTGCCCGGCACCGCCCCTAAGCTGCTGATCTATAAGAACTATAATAGGCCTAGCGGCGTGCCCGATAGGTTTAGCGGATCTAAATCAGGGACTTCTGCTAGTCTGGCTATTAGCGGCCTGCAGTCAGAGGACGAGGCCGACTACTACTGTAGCGCCTGGGATCAGCGTCAGTTCGACGTGGTGTTCGGCGGAGGCACTAAGCTGACCGTGCTGGGTCAACCTAAGGCTGCCCCCAGCGTGACCCTGTTCCCCCCCAGCAGCGAGGAGCTGCAGGCCAACAAGGCCACCCTGGTGTGCCTGATCAGCGACTTCTACCCAGGCGCCGTGACCGTGGCCTGGAAGGCCGACAGCAGCCCCGTGAAGGCCGGCGTGGAGACCACCACCCCCAGCAAGCAGAGCAACAACAAGTACGCCGCCAGCAGCTACCTGAGCCTGACCCCCGAGCAGTGGAAGAGCCACAGGTCCTACAGCTGCCAGGTGACCCACGAGGGCAGCACCGTGGAAAAGACCGTGGCCCCAACCGAGTGC AGC NOV1090 HCDR1   3GFTFSTAAMS (Combined) HCDR2   4 GISGSGSSTYYADSVKG (Combined) HCDR3   5ELSYLYSGYYFDY (Combined) HCDR1 (Kabat)   6 TAAMS HCDR2 (Kabat)   4GISGSGSSTYYADSVKG HCDR3 (Kabat)   5 ELSYLYSGYYFDY HCDR1   7 GFTFSTA(Chothia) HCDR2   8 SGSGSS (Chothia) HCDR3   5 ELSYLYSGYYFDY (Chothia)HCDR1 (IMGT)   9 GFTFSTAA HCDR2 (IMGT)  10 ISGSGSST HCDR3 (IMGT)  11ARELSYLYSGYYFDY VH  12 QVQLLESGGGLVQPGGSLRLSCAASGFTFSTAAMSWVRQAPGKGLEWVSGISGSGSSTYYADSVKGRFTISRDNSKNTLYLQMNSLRAEDTAVYYCARELSYLYSGYYFDYWGQGTLVTVSS DNA encoding VH 390CAGGTGCAATTGCTGGAAAGCGGCGGTGGCCTGGTGCAGCCGGGTGGCAGCCTGCGTCTGAGCTGCGCGGCGTCCGGATTCACCTTTTCTACTGCTGCTATGTCTTGGGTGCGCCAGGCCCCGGGCAAAGGTCTCGAGTGGGTTTCCGGTATCTCTGGTTCTGGTTCTTCTACCTACTATGCGGATAGCGTGAAAGGCCGCTTTACCATCAGCCGCGATAATTCGAAAAACACCCTGTATCTGCAAATGAACAGCCTGCGTGCGGAAGATACGGCCGTGTATTATTGCGCGCGTGAACTGTCTTACCTGTACTCTGGTTACTACTTCGATTACTGGGGCCAAGG CACCCTGGTGACTGTTAGCTCAHeavy Chain 360 QVQLLESGGGLVQPGGSLRLSCAASGFTFSTAAMSWVRQAPGKGLEWVSGISGSGSSTYYADSVKGRFTISRDNSKNTLYLQMNSLRAEDTAVYYCARELSYLYSGYYFDYWGQGTLVTVSSASTKGPSVFPLAPSSKSTSGGTAALGCLVKDYFPEPVTVSWNSGALTSGVHTFPAVLQSSGLYSLSSVVTVPSSSLGTQTYICNVNHKPSNTKVDKRVEPKSCDKTHTCPPCPAPEAAGGPSVFLFPPKPKDTLMISRTPEVTCVVVDVSHEDPEVKFNWYVDGVEVHNAKTKPREEQYNSTYRVVSVLTVLHQDWLNGKEYKCKVSNKALPAPIEKTISKAKGQPREPQVYTLPPSREEMTKNQVSLTCLVKGFYPSDIAVEWESNGQPENNYKTTPPVLDSDGSFFLYSKLTVDKSRWQQGNVFSC SVMHEALHNHYTQKSLSLSPGKDNA encoding 361 CAGGTGCAATTGCTGGAAAGCGGCGGTGGCCTGGTGCAGCCGG Heavy ChainGTGGCAGCCTGCGTCTGAGCTGCGCGGCGTCCGGATTCACCTTTTCTACTGCTGCTATGTCTTGGGTGCGCCAGGCCCCGGGCAAAGGTCTCGAGTGGGTTTCCGGTATCTCTGGTTCTGGTTCTTCTACCTACTATGCGGATAGCGTGAAAGGCCGCTTTACCATCAGCCGCGATAATTCGAAAAACACCCTGTATCTGCAAATGAACAGCCTGCGTGCGGAAGATACGGCCGTGTATTATTGCGCGCGTGAACTGTCTTACCTGTACTCTGGTTACTACTTCGATTACTGGGGCCAAGGCACCCTGGTGACTGTTAGCTCAGCCTCCACCAAGGGTCCATCGGTCTTCCCCCTGGCACCCTCCTCCAAGAGCACCTCTGGGGGCACAGCGGCCCTGGGCTGCCTGGTCAAGGACTACTTCCCCGAACCGGTGACGGTGTCGTGGAACTCAGGCGCCCTGACCAGCGGCGTGCACACCTTCCCGGCTGTCCTACAGTCCTCAGGACTCTACTCCCTCAGCAGCGTGGTGACCGTGCCCTCCAGCAGCTTGGGCACCCAGACCTACATCTGCAACGTGAATCACAAGCCCAGCAACACCAAGGTGGACAAGAGAGTTGAGCCCAAATCTTGTGACAAAACTCACACATGCCCACCGTGCCCAGCACCTGAAGCAGCGGGGGGACCGTCAGTCTTCCTCTTCCCCCCAAAACCCAAGGACACCCTCATGATCTCCCGGACCCCTGAGGTCACATGCGTGGTGGTGGACGTGAGCCACGAAGACCCTGAGGTCAAGTTCAACTGGTACGTGGACGGCGTGGAGGTGCATAATGCCAAGACAAAGCCGCGGGAGGAGCAGTACAACAGCACGTACCGGGTGGTCAGCGTCCTCACCGTCCTGCACCAGGACTGGCTGAATGGCAAGGAGTACAAGTGCAAGGTCTCCAACAAAGCCCTCCCAGCCCCCATCGAGAAAACCATCTCCAAAGCCAAAGGGCAGCCCCGAGAACCACAGGTGTACACCCTGCCCCCATCCCGGGAGGAGATGACCAAGAACCAGGTCAGCCTGACCTGCCTGGTCAAAGGCTTCTATCCCAGCGACATCGCCGTGGAGTGGGAGAGCAATGGGCAGCCGGAGAACAACTACAAGACCACGCCTCCCGTGCTGGACTCCGACGGCTCCTTCTTCCTCTACAGCAAGCTCACCGTGGACAAGAGCAGGTGGCAGCAGGGGAACGTCTTCTCATGCTCCGTGATGCATGAGGCTCTGCACAACCACTACACGCAGAAGA GCCTCTCCCTGTCTCCGGGTAAALCDR1  16 SGSSSNIGSNDVS (Combined) LCDR2  17 KNYNRPS (Combined) LCDR3 18 SAWDQRQFDVV (Combined) LCDR1 (Kabat)  16 SGSSSNIGSNDVS LCDR2 (Kabat) 17 KNYNRPS LCDR3 (Kabat)  18 SAWDQRQFDVV LCDR1  19 SSSNIGSND (Chothia)LCDR2  20 KNY (Chothia) LCDR3  21 WDQRQFDV (Chothia) LCDR1 (IMGT)  22SSNIGSND LCDR2 (IMGT)  20 KNY LCDR3 (IMGT)  18 SAWDQRQFDVV VL 362DIVLTQPPSVSGAPGQRVTISCSGSSSNIGSNDVSWYQQLPGTAPKLLIYKNYNRPSGVPDRFSGSKSGTSASLAITGLQAEDEAD YYCSAWDQRQFDVVFGGGTKLTVLDNA encoding VL 363 GATATCGTGCTGACCCAGCCGCCGAGCGTGAGCGGTGCACCGGGCCAGCGCGTGACCATTAGCTGTAGCGGCAGCAGCAGCAACATTGGTTCTAACGACGTGTCTTGGTACCAGCAGCTGCCGGGCACGGCGCCGAAACTGCTGATCTACAAAAACTACAACCGCCCGAGCGGCGTGCCGGATCGCTTTAGCGGATCCAAAAGCGGCACCAGCGCCAGCCTGGCGATTACCGGCCTGCAAGCAGAAGACGAAGCGGATTATTACTGCTCTGCTTGGGACCAGCGTCAGTTCGACGTTGTGTTTGGCGGCGGCACGAAGTTAACCGTCCTA Light Chain 364DIVLTQPPSVSGAPGQRVTISCSGSSSNIGSNDVSWYQQLPGTAPKLLIYKNYNRPSGVPDRFSGSKSGTSASLAITGLQAEDEADYYCSAWDQRQFDVVFGGGTKLTVLGQPKAAPSVTLFPPSSEELQANKATLVCLISDFYPGAVTVAWKADSSPVKAGVETTTPSKQSNNKYAASSYLSLTPEQWKSHRSYSCQVTHEGSTVEKTVAPTEC S DNA encoding 365GATATCGTGCTGACCCAGCCGCCGAGCGTGAGCGGTGCACCGG Light ChainGCCAGCGCGTGACCATTAGCTGTAGCGGCAGCAGCAGCAACATTGGTTCTAACGACGTGTCTTGGTACCAGCAGCTGCCGGGCACGGCGCCGAAACTGCTGATCTACAAAAACTACAACCGCCCGAGCGGCGTGCCGGATCGCTTTAGCGGATCCAAAAGCGGCACCAGCGCCAGCCTGGCGATTACCGGCCTGCAAGCAGAAGACGAAGCGGATTATTACTGCTCTGCTTGGGACCAGCGTCAGTTCGACGTTGTGTTTGGCGGCGGCACGAAGTTAACCGTCCTAGGTCAGCCCAAGGCTGCCCCCTCGGTCACTCTGTTCCCGCCCTCCTCTGAGGAGCTTCAAGCCAACAAGGCCACACTGGTGTGTCTCATAAGTGACTTCTACCCGGGAGCCGTGACAGTGGCCTGGAAGGCAGATAGCAGCCCCGTCAAGGCGGGAGTGGAGACCACCACACCCTCCAAACAAAGCAACAACAAGTACGCGGCCAGCAGCTATCTGAGCCTGACGCCTGAGCAGTGGAAGTCCCACAGAAGCTACAGCTGCCAGGTCACGCATGAAGGGAGCACCGTGGAGAAGACAGTGGCCCCTACAGAATGT TCA AM1 HCDR1   3 GFTFSTAAMS(Combined) HCDR2 366 TIDSWGDDTDYADSVKG (Combined) HCDR3   5ELSYLYSGYYFDY (Combined) HCDR1 (Kabat)   6 TAAMS HCDR2 (Kabat) 366TIDSWGDDTDYADSVKG HCDR3 (Kabat)   5 ELSYLYSGYYFDY HCDR1   7 GFTFSTA(Chothia) HCDR2 367 DSWGDD (Chothia) HCDR3   5 ELSYLYSGYYFDY (Chothia)HCDR1 (IMGT)   9 GFTFSTAA HCDR2 (IMGT) 368 IDSWGDDT HCDR3 (IMGT)  11ARELSYLYSGYYFDY VH 369 QVQLLESGGGLVQPGGSLRLSCAASGFTFSTAAMSWVRQAPGKGLEMVSTIDSWGDDIDYADSVKGRFTISRDNSKNTLYLQMNSLRAEDTAVYYCARELSYLYSGYYFDYWGQGTLVTVSS DNA VH 370CAGGTGCAATTGCTGGAAAGCGGCGGTGGCCTGGTGCAGCCGGGTGGCAGCCTGCGTCTGAGCTGCGCGGCGTCCGGATTCACCTTTTCTACTGCTGCTATGTCTTGGGTGCGCCAGGCCCCGGGCAAAGGTCTCGAGTGGGTTTCCACTATCGACTCTTGGGGCGACGACACTGACTATGCGGATAGCGTGAAAGGCCGCTTTACCATCAGCCGCGATAATTCGAAAAACACCCTGTATCTGCAAATGAACAGCCTGCGTGCGGAAGATACGGCCGTGTATTATTGCGCGCGTGAACTGTCTTACCTGTACTCTGGTTACTACTTCGATTACTGGGGCCAAGG CACCCTGGTGACTGTTAGCTCAHeavy Chain 371 QVQLLESGGGLVQPGGSLRLSCAASGFTFSTAAMSWVRQAPGKGLEMVSTIDSWGDDIDYADSVKGRFTISRDNSKNTLYLQMNSLRAEDTAVYYCARELSYLYSGYYFDYWGQGTLVTVSSASTKGPSVFPLAPSSKSTSGGTAALGCLVKDYFPEPVTVSWNSGALTSGVHTFPAVLQSSGLYSLSSVVTVPSSSLGTQTYICNVNHKPSNTKVDKRVEPKSCDKTHTCPPCPAPEAAGGPSVFLFPPKPKDTLMISRTPEVTCVVVDVSHEDPEVKFNWYVDGVEVHNAKTKPREEQYNSTYRVVSVLTVLHQDWLNGKEYKCKVSNKALPAPIEKTISKAKGQPREPQVYTLPPSREEMTKNQVSLTCLVKGFYPSDIAVEWESNGQPENNYKTTPPVLDSDGSFFLYSKLTVDKSRWQQGNVFSC SVMHEALHNHYTQKSLSLSPGKDNA Heavy 391 CAGGTGCAATTGCTGGAAAGCGGCGGTGGCCTGGTGCAGCCGG ChainGTGGCAGCCTGCGTCTGAGCTGCGCGGCGTCCGGATTCACCTTTTCTACTGCTGCTATGTCTTGGGTGCGCCAGGCCCCGGGCAAAGGTCTCGAGTGGGTTTCCACTATCGACTCTTGGGGCGACGACACTGACTATGCGGATAGCGTGAAAGGCCGCTTTACCATCAGCCGCGATAATTCGAAAAACACCCTGTATCTGCAAATGAACAGCCTGCGTGCGGAAGATACGGCCGTGTATTATTGCGCGCGTGAACTGTCTTACCTGTACTCTGGTTACTACTTCGATTACTGGGGCCAAGGCACCCTGGTGACTGTTAGCTCAGCCTCCACCAAGGGTCCATCGGTCTTCCCCCTGGCACCCTCCTCCAAGAGCACCTCTGGGGGCACAGCGGCCCTGGGCTGCCTGGTCAAGGACTACTTCCCCGAACCGGTGACGGTGTCGTGGAACTCAGGCGCCCTGACCAGCGGCGTGCACACCTTCCCGGCTGTCCTACAGTCCTCAGGACTCTACTCCCTCAGCAGCGTGGTGACCGTGCCCTCCAGCAGCTTGGGCACCCAGACCTACATCTGCAACGTGAATCACAAGCCCAGCAACACCAAGGTGGACAAGAGAGTTGAGCCCAAATCTTGTGACAAAACTCACACATGCCCACCGTGCCCAGCACCTGAAGCAGCGGGGGGACCGTCAGTCTTCCTCTTCCCCCCAAAACCCAAGGACACCCTCATGATCTCCCGGACCCCTGAGGTCACATGCGTGGTGGTGGACGTGAGCCACGAAGACCCTGAGGTCAAGTTCAACTGGTACGTGGACGGCGTGGAGGTGCATAATGCCAAGACAAAGCCGCGGGAGGAGCAGTACAACAGCACGTACCGGGTGGTCAGCGTCCTCACCGTCCTGCACCAGGACTGGCTGAATGGCAAGGAGTACAAGTGCAAGGTCTCCAAACAAAGCCCTCCCAGCCCCCATCGAGAAAACCATCTCCAAAGCCAAAGGGCAGCCCCGAGAACCACAGGTGTACACCCTGCCCCCATCCCGGGAGGAGATGACCAAGAACCAGGTCAGCCTGACCTGCCTGGTCAAAGGCTTCTATCCCAGCGACATCGCCGTGGAGTGGGAGAGCAATGGGCAGCCGGAGAACAACTACAAGACCACGCCTCCCGTGCTGGACTCCGACGGCTCCTTCTTCCTCTACAGCAAGCTCACCGTGGACAAGAGCAGGTGGCAGCAGGGGAACGTCTTCTCATGTGCTCCGTGATGCATGAGGCTCTGCACAACCACTACACGCAGA AGAGCCTCTCCCTGTCTCCGGGTAAALCDR1  16 SGSSSNIGSNDVS (Combined) LCDR2  17 KNYNRPS (Combined) LCDR3 18 SAWDQRQFDVV (Combined) LCDR1 (Kabat)  16 SGSSSNIGSNDVS LCDR2 (Kabat) 17 KNYNRPS LCDR3 (Kabat)  18 SAWDQRQFDVV LCDR1  19 SSSNIGSND (Chothia)LCDR2  20 KNY (Chothia) LCDR3  21 WDQRQFDV (Chothia) LCDR1 (IMGT)  22SSNIGSND LCDR2 (IMGT)  20 KNY LCDR3 (IMGT)  18 SAWDQRQFDVV VL 362DIVLTQPPSVSGAPGQRVTISCSGSSSNIGSNDVSWYQQLPGTAPKLLIYKNYNRPSGVPDRFSGSKSGTSASLAITGLQAEDEAD YYCSAWDQRQFDVVFGGGTKLTVLDNA VL 363 GATATCGTGCTGACCCAGCCGCCGAGCGTGAGCGGTGCACCGGGCCAGCGCGTGACCATTAGCTGTAGCGGCAGCAGCAGCAACATTGGTTCTAACGACGTGTCTTGGTACCAGCAGCTGCCGGGCACGGCGCCGAAACTGCTGATCTACAAAAACTACAACCGCCCGAGCGGCGTGCCGGATCGCTTTAGCGGATCCAAAAGCGGCACCAGCGCCAGCCTGGCGATTACCGGCCTGCAAGCAGAAGACGAAGCGGATTATTACTGCTCTGCTTGGGACCAGCGTCAGTTCGACGTTGTGTTTGGCGGCGGCACGAAGTTAACCGTCCTA Light Chain 364DIVLTQPPSVSGAPGQRVTISCSGSSSNIGSNDVSWYQQLPGTAPKLLIYKNYNRPSGVPDRFSGSKSGTSASLAITGLQAEDEADYYCSAWDQRQFDVVFGGGTKLTVLGQPKAAPSVTLFPPSSEELQANKATLVCLISDFYPGAVTVAWKADSSPVKAGVETTTPSKQSNNKYAASSYLSLTPEQWKSHRSYSCQVTHEGSTVEKTVAPTEC S DNA Light 365GATATCGTGCTGACCCAGCCGCCGAGCGTGAGCGGTGCACCGG ChainGCCAGCGCGTGACCATTAGCTGTAGCGGCAGCAGCAGCAACATTGGTTCTAACGACGTGTCTTGGTACCAGCAGCTGCCGGGCACGGCGCCGAAACTGCTGATCTACAAAAACTACAACCGCCCGAGCGGCGTGCCGGATCGCTTTAGCGGATCCAAAAGCGGCACCAGCGCCAGCCTGGCGATTACCGGCCTGCAAGCAGAAGACGAAGCGGATTATTACTGCTCTGCTTGGGACCAGCGTCAGTTCGACGTTGTGTTTGGCGGCGGCACGAAGTTAACCGTCCTAGGTCAGCCCAAGGCTGCCCCCTCGGTCACTCTGTTCCCGCCCTCCTCTGAGGAGCTTCAAGCCAACAAGGCCACACTGGTGTGTCTCATAAGTGACTTCTACCCGGGAGCCGTGACAGTGGCCTGGAAGGCAGATAGCAGCCCCGTCAAGGCGGGAGTGGAGACCACCACACCCTCCAAACAAAGCAACAACAAGTACGCGGCCAGCAGCTATCTGAGCCTGACGCCTGAGCAGTGGAAGTCCCACAGAAGCTACAGCTGCCAGGTCACGCATGAAGGGAGCACCGTGGAGAAGACAGTGGCCCCTACAGAATGT TCA AM2 HCDR1   3 GFTFSTAAMS(Combined) HCDR2 372 SIEYYDTDTHYADSVKG (Combined) HCDR3   5ELSYLYSGYYFDY (Combined) HCDR1 (Kabat)   6 TAAMS HCDR2 (Kabat) 372SIEYYDTDTHYADSVKG HCDR3 (Kabat)   5 ELSYLYSGYYFDY HCDR1   7 GFTFSTA(Chothia) HCDR2 373 EYYDTD (Chothia) HCDR3   5 ELSYLYSGYYFDY (Chothia)HCDR1 (IMGT)   9 GFTFSTAA HCDR2 (IMGT) 374 IEYYDTDT HCDR3 (IMGT)  11ARELSYLYSGYYFDY VH 375 QVQLLESGGGLVQPGGSLRLSCAASGFTFSTAAMSWVRQAPGKGLEWVSSIEYYDTDTHYADSVKGRFTISRDNSKNTLYLQMNSLRAEDTAVYYCARELSYLYSGYYFDYWGQGTLVTVSS DNA VH 376CAGGTGCAATTGCTGGAAAGCGGCGGTGGCCTGGTGCAGCCGGGTGGCAGCCTGCGTCTGAGCTGCGCGGCGTCCGGATTCACCTTTTCTACTGCTGCTATGTCTTGGGTGCGCCAGGCCCCGGGCAAAGGTCTCGAGTGGGTTTCCTCTATCGAATACTACGACACTGACACTCATTATGCGGATAGCGTGAAAGGCCGCTTTACCATCAGCCGCGATAATTCGAAAAACACCCTGTATCTGCAAATGAACAGCCTGCGTGCGGAAGATACGGCCGTGTATTATTGCGCGCGTGAACTGTCTTACCTGTACTCTGGTTACTACTTCGATTACTGGGGCCAAGG CACCCTGGTGACTGTTAGCTCAHeavy Chain 377 QVQLLESGGGLVQPGGSLRLSCAASGFTFSTAAMSWVRQAPGKGLEWVSSIEYYDTDTHYADSVKGRFTISRDNSKNTLYLQMNSLRAEDTAVYYCARELSYLYSGYYFDYWGQGTLVTVSSASTKGPSVFPLAPSSKSTSGGTAALGCLVKDYFPEPVTVSWNSGALTSGVHTFPAVLQSSGLYSLSSVVTVPSSSLGTQTYICNVNHKPSNTKVDKRVEPKSCDKTHTCPPCPAPEAAGGPSVFLFPPKPKDTLMISRTPEVTCVVVDVSHEDPEVKFNWYVDGVEVHNAKTKPREEQYNSTYRVVSVLTVLHQDWLNGKEYKCKVSNKALPAPIEKTISKAKGQPREPQVYTLPPSREEMTKNQVSLTCLVKGFYPSDIAVEWESNGQPENNYKTTPPVLDSDGSFFLYSKLTVDKSRWQQGNVFSC SVMHEALHNHYTQKSLSLSPGKDNA Heavy 378 CAGGTGCAATTGCTGGAAAGCGGCGGTGGCCTGGTGCAGCCGG ChainGTGGCAGCCTGCGTCTGAGCTGCGCGGCGTCCGGATTCACCTTTTCTACTGCTGCTATGTCTTGGGTGCGCCAGGCCCCGGGCAAAGGTCTCGAGTGGGTTTCCTCTATCGAATACTACGACACTGACACTCATTATGCGGATAGCGTGAAAGGCCGCTTTACCATCAGCCGCGATAATTCGAAAAACACCCTGTATCTGCAAATGAACAGCCTGCGTGCGGAAGATACGGCCGTGTATTATTGCGCGCGTGAACTGTCTTACCTGTACTCTGGTTACTACTTCGATTACTGGGGCCAAGGCACCCTGGTGACTGTTAGCTCAGCCTCCACCAAGGGTCCATCGGTCTTCCCCCTGGCACCCTCCTCCAAGAGCACCTCTGGGGGCACAGCGGCCCTGGGCTGCCTGGTCAAGGACTACTTCCCCGAACCGGTGACGGTGTCGTGGAACTCAGGCGCCCTGACCAGCGGCGTGCACACCTTCCCGGCTGTCCTACAGTCCTCAGGACTCTACTCCCTCAGCAGCGTGGTGACCGTGCCCTCCAGCAGCTTGGGCACCCAGACCTACATCTGCAACGTGAATCACAAGCCCAGCAACACCAAGGTGGACAAGAGAGTTGAGCCCAAATCTTGTGACAAAACTCACACATGCCCACCGTGCCCAGCACCTGAAGCAGCGGGGGGACCGTCAGTCTTCCTCTTCCCCCCAAAACCCAAGGACACCCTCATGATCTCCCGGACCCCTGAGGTCACATGCGTGGTGGTGGACGTGAGCCACGAAGACCCTGAGGTCAAGTTCAACTGGTACGTGGACGGCGTGGAGGTGCATAATGCCAAGACAAAGCCGCGGGAGGAGCAGTACAACAGCACGTACCGGGTGGTCAGCGTCCTCACCGTCCTGCACCAGGACTGGCTGAATGGCAAGGAGTACAAGTGCAAGGTCTCCAACAAAGCCCTCCCAGCCCCCATCGAGAAAACCATCTCCAAAGCCAAAGGGCAGCCCCGAGAACCACAGGTGTACACCCTGCCCCCATCCCGGGAGGAGATGACCAAGAACCAGGTCAGCCTGACCTGCCTGGTCAAAGGCTTCTATCCCAGCGACATCGCCGTGGAGTGGGAGAGCAATGGGCAGCCGGAGAACAACTACAAGACCACGCCTCCCGTGCTGGACTCCGACGGCTCCTTCTTCCTCTACAGCAAGCTCACCGTGGACAAGAGCAGGTGGCAGCAGGGGAACGTCTTCTCATGCTCCGTGATGCATGAGGCTCTGCACAACCACTACACGCAGAAGA GCCTCTCCCTGTCTCCGGGTAAALCDR1  16 SGSSSNIGSNDVS (Combined) LCDR2  17 KNYNRPS (Combined) LCDR3 18 SAWDQRQFDVV (Combined) LCDR1 (Kabat)  16 SGSSSNIGSNDVS LCDR2 (Kabat) 17 KNYNRPS LCDR3 (Kabat)  18 SAWDQRQFDVV LCDR1  19 SSSNIGSND (Chothia)LCDR2  20 KNY (Chothia) LCDR3  21 WDQRQFDV (Chothia) LCDR1 (IMGT)  22SSNIGSND LCDR2 (IMGT)  20 KNY LCDR3 (IMGT)  18 SAWDQRQFDVV VL 362DIVLTQPPSVSGAPGQRVTISCSGSSSNIGSNDVSWYQQLPGTAPKLLIYKNYNRPSGVPDRFSGSKSGTSASLAITGLQAEDEAD YYCSAWDQRQFDVVFGGGTKLTVLDNA VL 363 GATATCGTGCTGACCCAGCCGCCGAGCGTGAGCGGTGCACCGGGCCAGCGCGTGACCATTAGCTGTAGCGGCAGCAGCAGCAACATTGGTTCTAACGACGTGTCTTGGTACCAGCAGCTGCCGGGCACGGCGCCGAAACTGCTGATCTACAAAAACTACAACCGCCCGAGCGGCGTGCCGGATCGCTTTAGCGGATCCAAAAGCGGCACCAGCGCCAGCCTGGCGATTACCGGCCTGCAAGCAGAAGACGAAGCGGATTATTACTGCTCTGCTTGGGACCAGCGTCAGTTCGACGTTGTGTTTGGCGGCGGCACGAAGTTAACCGTCCTA Light Chain 364DIVLTQPPSVSGAPGQRVTISCSGSSSNIGSNDVSWYQQLPGTAPKLLIYKNYNRPSGVPDRFSGSKSGTSASLAITGLQAEDEADYYCSAWDQRQFDVVFGGGTKLTVLGQPKAAPSVTLFPPSSEELQANKATLVCLISDFYPGAVTVAWKADSSPVKAGVETTTPSKQSNNKYAASSYLSLTPEQWKSHRSYSCQVTHEGSTVEKTVAPTEC S DNA Light 365GATATCGTGCTGACCCAGCCGCCGAGCGTGAGCGGTGCACCGG ChainGCCAGCGCGTGACCATTAGCTGTAGCGGCAGCAGCAGCAACATTGGTTCTAACGACGTGTCTTGGTACCAGCAGCTGCCGGGCACGGCGCCGAAACTGCTGATCTACAAAAACTACAACCGCCCGAGCGGCGTGCCGGATCGCTTTAGCGGATCCAAAAGCGGCACCAGCGCCAGCCTGGCGATTACCGGCCTGCAAGCAGAAGACGAAGCGGATTATTACTGCTCTGCTTGGGACCAGCGTCAGTTCGACGTTGTGTTTGGCGGCGGCACGAAGTTAACCGTCCTAGGTCAGCCCAAGGCTGCCCCCTCGGTCACTCTGTTCCCGCCCTCCTCTGAGGAGCTTCAAGCCAACAAGGCCACACTGGTGTGTCTCATAAGTGACTTCTACCCGGGAGCCGTGACAGTGGCCTGGAAGGCAGATAGCAGCCCCGTCAAGGCGGGAGTGGAGACCACCACACCCTCCAAACAAAGCAACAACAAGTACGCGGCCAGCAGCTATCTGAGCCTGACGCCTGAGCAGTGGAAGTCCCACAGAAGCTACAGCTGCCAGGTCACGCATGAAGGGAGCACCGTGGAGAAGACAGTGGCCCCTACAGAATGT TCA AM3 HCDR1   3 GFTFSTAAMS(Combined) HCDR2 379 TIEYSSQETYYADSVKG (Combined) HCDR3   5ELSYLYSGYYFDY (Combined) HCDR1 (Kabat)   6 TAAMS HCDR2 (Kabat) 379TIEYSSQETYYADSVKG HCDR3 (Kabat)   5 ELSYLYSGYYFDY HCDR1   7 GFTFSTA(Chothia) HCDR2 380 EYSSQE (Chothia) HCDR3   5 ELSYLYSGYYFDY (Chothia)HCDR1 (IMGT)   9 GFTFSTAA HCDR2 (IMGT) 381 IEYSSQET HCDR3 (IMGT)  11ARELSYLYSGYYFDY VH 382 QVQLLESGGGLVQPGGSLRLSCAASGFTFSTAAMSWVRQAPGKGLEWVSTIEYSSQETYYADSVKGRFTISRDNSKNTLYLQMNSLRAEDTAVYYCARELSYLYSGYYFDYWGQGTLVTVSS DNA VH 383CAGGTGCAATTGCTGGAAAGCGGCGGTGGCCTGGTGCAGCCGGGTGGCAGCCTGCGTCTGAGCTGCGCGGCGTCCGGATTCACCTTTTCTACTGCTGCTATGTCTTGGGTGCGCCAGGCCCCGGGCAAAGGTCTCGAGTGGGTTTCCACTATCGAATACTCTAGCCAGGAAACTTACTATGCGGATAGCGTGAAAGGCCGCTTTACCATCAGCCGCGATAATTCGAAAAACACCCTGTATCTGCAAATGAACAGCCTGCGTGCGGAAGATACGGCCGTGTATTATTGCGCGCGTGAACTGTCTTACCTGTACTCTGGTTACTACTTCGATTACTGGGGCCAAGG CACCCTGGTGACTGTTAGCTCAHeavy Chain 384 QVQLLESGGGLVQPGGSLRLSCAASGFTFSTAAMSWVRQAPGKGLEWVSTIEYSSQETYYADSVKGRFTISRDNSKNTLYLQMNSLRAEDTAVYYCARELSYLYSGYYFDYWGQGTLVTVSSASTKGPSVFPLAPSSKSTSGGTAALGCLVKDYFPEPVTVSWNSGALTSGVHTFPAVLQSSGLYSLSSVVTVPSSSLGTQTYICNVNHKPSNTKVDKRVEPKSCDKTHTCPPCPAPEAAGGPSVFLFPPKPKDTLMISRTPEVTCVVVDVSHEDPEVKFNWYVDGVEVHNAKTKPREEQYNSTYRVVSVLTVLHQDWLNGKEYKCKVSNKALPAPIEKTISKAKGQPREPQVYTLPPSREEMTKNQVSLTCLVKGFYPSDIAVEWESNGQPENNYKTTPPVLDSDGSFFLYSKLTVDKSRWQQGNVFSC SVMHEALHNHYTQKSLSLSPGKDNA Heavy 385 CAGGTGCAATTGCTGGAAAGCGGCGGTGGCCTGGTGCAGCCGG ChainGTGGCAGCCTGCGTCTGAGCTGCGCGGCGTCCGGATTCACCTTTTCTACTGCTGCTATGTCTTGGGTGCGCCAGGCCCCGGGCAAAGGTCTCGAGTGGGTTTCCACTATCGAATACTCTAGCCAGGAAACTTACTATGCGGATAGCGTGAAAGGCCGCTTTACCATCAGCCGCGATAATTCGAAAAACACCCTGTATCTGCAAATGAACAGCCTGCGTGCGGAAGATACGGCCGTGTATTATTGCGCGCGTGAACTGTCTTACCTGTACTCTGGTTACTACTTCGATTACTGGGGCCAAGGCACCCTGGTGACTGTTAGCTCAGCCTCCACCAAGGGTCCATCGGTCTTCCCCCTGGCACCCTCCTCCAAGAGCACCTCTGGGGGCACAGCGGCCCTGGGCTGCCTGGTCAAGGACTACTTCCCCGAACCGGTGACGGTGTCGTGGAACTCAGGCGCCCTGACCAGCGGCGTGCACACCTTCCCGGCTGTCCTACAGTCCTCAGGACTCTACTCCCTCAGCAGCGTGGTGACCGTGCCCTCCAGCAGCTTGGGCACCCAGACCTACATCTGCAACGTGAATCACAAGCCCAGCAACACCAAGGTGGACAAGAGAGTTGAGCCCAAATCTTGTGACAAAACTCACACATGCCCACCGTGCCCAGCACCTGAAGCAGCGGGGGGACCGTCAGTCTTCCTCTTCCCCCCAAAACCCAAGGACACCCTCATGATCTCCCGGACCCCTGAGGTCACATGCGTGGTGGTGGACGTGAGCCACGAAGACCCTGAGGTCAAGTTCAACTGGTACGTGGACGGCGTGGAGGTGCATAATGCCAAGACAAAGCCGCGGGAGGAGCAGTACAACAGCACGTACCGGGTGGTCAGCGTCCTCACCGTCCTGCACCAGGACTGGCTGAATGGCAAGGAGTACAAGTGCAAGGTCTCCAACAAAGCCCTCCCAGCCCCCATCGAGAAAACCATCTCCAAAGCCAAAGGGCAGCCCCGAGAACCACAGGTGTACACCCTGCCCCCATCCCGGGAGGAGATGACCAAGAACCAGGTCAGCCTGACCTGCCTGGTCAAAGGCTTCTATCCCAGCGACATCGCCGTGGAGTGGGAGAGCAATGGGCAGCCGGAGAACAACTACAAGACCACGCCTCCCGTGCTGGACTCCGACGGCTCCTTCTTCCTCTACAGCAAGCTCACCGTGGACAAGAGCAGGTGGCAGCAGGGGAACGTCTTCTCATGCTCCGTGATGCATGAGGCTCTGCACAACCACTACACGCAGAAGA GCCTCTCCCTGTCTCCGGGTAAALCDR1  16 SGSSSNIGSNDVS (Combined) LCDR2  17 KNYNRPS (Combined) LCDR3 18 SAWDQRQFDVV (Combined) LCDR1 (Kabat)  16 SGSSSNIGSNDVS LCDR2 (Kabat) 17 KNYNRPS LCDR3 (Kabat)  18 SAWDQRQFDVV LCDR1  19 SSSNIGSND (Chothia)LCDR2  20 KNY (Chothia) LCDR3  21 WDQRQFDV (Chothia) LCDR1 (IMGT)  22SSNIGSND LCDR2 (IMGT)  20 KNY LCDR3 (IMGT)  18 SAWDQRQFDVV VL 362DIVLTQPPSVSGAPGQRVTISCSGSSSNIGSNDVSWYQQLPGTAPKLLIYKNYNRPSGVPDRFSGSKSGTSASLAITGLQAEDEAD YYCSAWDQRQFDVVFGGGTKLTVLDNA VL 363 GATATCGTGCTGACCCAGCCGCCGAGCGTGAGCGGTGCACCGGGCCAGCGCGTGACCATTAGCTGTAGCGGCAGCAGCAGCAACATTGGTTCTAACGACGTGTCTTGGTACCAGCAGCTGCCGGGCACGGCGCCGAAACTGCTGATCTACAAAAACTACAACCGCCCGAGCGGCGTGCCGGATCGCTTTAGCGGATCCAAAAGCGGCACCAGCGCCAGCCTGGCGATTACCGGCCTGCAAGCAGAAGACGAAGCGGATTATTACTGCTCTGCTTGGGACCAGCGTCAGTTCGACGTTGTGTTTGGCGGCGGCACGAAGTTAACCGTCCTA Light Chain 364DIVLTQPPSVSGAPGQRVTISCSGSSSNIGSNDVSWYQQLPGTAPKLLIYKNYNRPSGVPDRFSGSKSGTSASLAITGLQAEDEADYYCSAWDQRQFDVVFGGGTKLTVLGQPKAAPSVTLFPPSSEELQANKATLVCLISDFYPGAVTVAWKADSSPVKAGVETTTPSKQSNNKYAASSYLSLTPEQWKSHRSYSCQVTHEGSTVEKTVAPTEC S DNA Light 365GATATCGTGCTGACCCAGCCGCCGAGCGTGAGCGGTGCACCGG ChainGCCAGCGCGTGACCATTAGCTGTAGCGGCAGCAGCAGCAACATTGGTTCTAACGACGTGTCTTGGTACCAGCAGCTGCCGGGCACGGCGCCGAAACTGCTGATCTACAAAAACTACAACCGCCCGAGCGGCGTGCCGGATCGCTTTAGCGGATCCAAAAGCGGCACCAGCGCCAGCCTGGCGATTACCGGCCTGCAAGCAGAAGACGAAGCGGATTATTACTGCTCTGCTTGGGACCAGCGTCAGTTCGACGTTGTGTTTGGCGGCGGCACGAAGTTAACCGTCCTAGGTCAGCCCAAGGCTGCCCCCTCGGTCACTCTGTTCCCGCCCTCCTCTGAGGAGCTTCAAGCCAACAAGGCCACACTGGTGTGTCTCATAAGTGACTTCTACCCGGGAGCCGTGACAGTGGCCTGGAAGGCAGATAGCAGCCCCGTCAAGGCGGGAGTGGAGACCACCACACCCTCCAAACAAAGCAACAACAAGTACGCGGCCAGCAGCTATCTGAGCCTGACGCCTGAGCAGTGGAAGTCCCACAGAAGCTACAGCTGCCAGGTCACGCATGAAGGGAGCACCGTGGAGAAGACAGTGGCCCCTACAGAATGT TCA AM4 HCDR1   3 GFTFSTAAMS(Combined) HCDR2 379 TIEYSSQETYYADSVKG (Combined) HCDR3   5ELSYLYSGYYFDY (Combined) HCDR1 (Kabat)   6 TAAMS HCDR2 (Kabat) 379TIEYSSQETYYADSVKG HCDR3 (Kabat)   5 ELSYLYSGYYFDY HCDR1   7 GFTFSTA(Chothia) HCDR2 380 EYSSQE (Chothia) HCDR3   5 ELSYLYSGYYFDY (Chothia)HCDR1 (IMGT)   9 GFTFSTAA HCDR2 (IMGT) 381 IEYSSQET HCDR3 (IMGT)  11ARELSYLYSGYYFDY VH 382 QVQLLESGGGLVQPGGSLRLSCAASGFTFSTAAMSWVRQAPGKGLEWVSTIEYSSQETYYADSVKGRFTISRDNSKNTLYLQMNSLRAEDTAVYYCARELSYLYSGYYFDYWGQGTLVTVSS DNA VH 392CAAGTGCAGCTGCTTGAATCTGGCGGCGGACTGGTGCAGCCTGGCGGCTCCCTGAGACTGTCTTGCGCCGCCTCCGGCTTCACCTTCTCCACCGCCGCTATGTCCTGGGTCCGACAGGCTCCCGGCAAGGGCCTGGAATGGGTGTCCACCATTGAGTACTCCAGCCAGGAAACCTACTACGCCGACTCCGTGAAGGGCCGGTTCACCATCTCCCGGGACAACTCCAAGAACACCCTGTACCTGCAGATGAACTCCCTGCGGGCCGAGGACACCGCCGTGTACTACTGCGCCAGAGAGCTGTCCTACCTGTACTCCGGCTACTACTTCGACTACTGGGGCCAGGG CACCCTGGTCACCGTGTCCTCTHeavy Chain 384 QVQLLESGGGLVQPGGSLRLSCAASGFTFSTAAMSWVRQAPGKGLEWVSTIEYSSQETYYADSVKGRFTISRDNSKNTLYLQMNSLRAEDTAVYYCARELSYLYSGYYFDYWGQGTLVTVSSASTKGPSVFPLAPSSKSTSGGTAALGCLVKDYFPEPVTVSWNSGALTSGVHTFPAVLQSSGLYSLSSVVTVPSSSLGTQTYICNVNHKPSNTKVDKRVEPKSCDKTHTCPPCPAPEAAGGPSVFLFPPKPKDTLMISRTPEVTCVVVDVSHEDPEVKFNWYVDGVEVHNAKTKPREEQYNSTYRVVSVLTVLHQDWLNGKEYKCKVSNKALPAPIEKTISKAKGQPREPQVYTLPPSREEMTKNQVSLTCLVKGFYPSDIAVEWESNGQPENNYKTTPPVLDSDGSFFLYSKLTVDKSRWQQGNVFSC SVMHEALHNHYTQKSLSLSPGKDNA Heavy 393 CAAGTGCAGCTGCTTGAATCTGGCGGCGGACTGGTGCAGCCTG ChainGCGGCTCCCTGAGACTGTCTTGCGCCGCCTCCGGCTTCACCTTCTCCACCGCCGCTATGTCCTGGGTCCGACAGGCTCCCGGCAAGGGCCTGGAATGGGTGTCCACCATTGAGTACTCCAGCCAGGAAACCTACTACGCCGACTCCGTGAAGGGCCGGTTCACCATCTCCCGGGACAACTCCAAGAACACCCTGTACCTGCAGATGAACTCCCTGCGGGCCGAGGACACCGCCGTGTACTACTGCGCCAGAGAGCTGTCCTACCTGTACTCCGGCTACTACTTCGACTACTGGGGCCAGGGCACCCTGGTCACCGTGTCCTCTGCTAGCACCAAGGGCCCCTCCGTGTTCCCTCTGGCCCCTTCCAGCAAGTCTACCTCCGGCGGCACAGCTGCTCTGGGCTGCCTGGTCAAGGACTACTTCCCTGAGCCTGTGACAGTGTCCTGGAACTCTGGCGCCCTGACCTCTGGCGTGCACACCTTCCCTGCCGTGCTGCAGTCCTCCGGCCTGTACTCCCTGTCCTCCGTGGTCACAGTGCCTTCAAGCAGCCTGGGCACCCAGACCTATATCTGCAACGTGAACCACAAGCCTTCCAACACCAAGGTGGACAAGCGGGTGGAGCCTAAGTCCTGCGACAAGACCCACACCTGTCCTCCCTGCCCTGCTCCTGAAGCTGCTGGCGGCCCTTCTGTGTTCCTGTTCCCTCCAAAGCCCAAGGACACCCTGATGATCTCCCGGACCCCTGAAGTGACCTGCGTGGTGGTGGACGTGTCCCACGAGGATCCTGAAGTGAAGTTCAATTGGTACGTGGACGGCGTGGAGGTGCACAACGCCAAGACCAAGCCTCGGGAGGAACAGTACAACTCCACCTACCGGGTGGTGTCCGTGCTGACCGTGCTGCACCAGGACTGGCTGAACGGCAAAGAGTACAAGTGCAAAGTCTCCAACAAGGCCCTGCCTGCCCCTATCGAAAAGACAATCTCCAAGGCCAAGGGCCAGCCTAGGGAACCCCAGGTGTACACCCTGCCACCCAGCCGGGAGGAAATGACCAAGAACCAGGTGTCCCTGACCTGTCTGGTCAAGGGCTTCTACCCTTCCGATATCGCCGTGGAGTGGGAGTCTAACGGCCAGCCTGAGAACAACTACAAGACCACCCCTCCTGTGCTGGACTCCGACGGCTCCTTCTTCCTGTACTCCAAACTGACCGTGGACAAGTCCCGGTGGCAGCAGGGCAACGTGTTCTCCTGCTCCGTGATGCACGAGGCCCTGCACAACCACTACACCCAGAAGT CCCTGTCCCTGTCTCCCGGCAAGLCDR1  16 SGSSSNIGSNDVS (Combined) LCDR2  17 KNYNRPS (Combined) LCDR3 18 SAWDQRQFDVV (Combined) LCDR1 (Kabat)  16 SGSSSNIGSNDVS LCDR2 (Kabat) 17 KNYNRPS LCDR3 (Kabat)  18 SAWDQRQFDVV LCDR1  19 SSSNIGSND (Chothia)LCDR2  20 KNY (Chothia) LCDR3  21 WDQRQFDV (Chothia) LCDR1 (IMGT)  22SSNIGSND LCDR2 (IMGT)  20 KNY LCDR3 (IMGT)  18 SAWDQRQFDVV VL 386QSVLTQPPSVSGAPGQRVTISCSGSSSNIGSNDVSWYQQLPGTAPKLLIYKNYNRPSGVPDRFSGSKSGTSASLAITGLQAEDEAD YYCSAWDQRQFDVVFGGGTKLTVLDNA VL 387 CAGAGCGTGCTGACACAGCCTCCCTCCGTGTCTGGCGCCCCTGGCCAGAGAGTGACCATCTCCTGCTCCGGCTCCTCCTCCAACATCGGCTCCAACGACGTGTCCTGGTATCAGCAGCTGCCCGGCACCGCCCCTAAGCTGCTGATCTACAAGAACTACAACCGGCCCTCCGGCGTGCCCGACCGGTTCTCTGGCTCCAAGTCTGGCACCTCCGCCTCCCTGGCTATCACCGGCCTGCAGGCTGAGGACGAGGCCGACTACTACTGCTCCGCCTGGGACCAGCGGCAGTTCGACGTGGTGTTCGGCGGAGGCACCAAGCTGACCGTGCTG Light Chain 388QSVLTQPPSVSGAPGQRVTISCSGSSSNIGSNDVSWYQQLPGTAPKLLIYKNYNRPSGVPDRFSGSKSGTSASLAITGLQAEDEADYYCSAWDQRQFDVVFGGGTKLTVLGQPKAAPSVTLFPPSSEELQANKATLVCLISDFYPGAVTVAWKADSSPVKAGVETTTPSKQSNNKYAASSYLSLTPEQWKSHRSYSCQVTHEGSTVEKTVAPTEC S DNA Light 389CAGAGCGTGCTGACACAGCCTCCCTCCGTGTCTGGCGCCCCTG ChainGCCAGAGAGTGACCATCTCCTGCTCCGGCTCCTCCTCCAACATCGGCTCCAACGACGTGTCCTGGTATCAGCAGCTGCCCGGCACCGCCCCTAAGCTGCTGATCTACAAGAACTACAACCGGCCCTCCGGCGTGCCCGACCGGTTCTCTGGCTCCAAGTCTGGCACCTCCGCCTCCCTGGCTATCACCGGCCTGCAGGCTGAGGACGAGGCCGACTACTACTGCTCCGCCTGGGACCAGCGGCAGTTCGACGTGGTGTTCGGCGGAGGCACCAAGCTGACCGTGCTGGGCCAGCCTAAGGCTGCCCCCAGCGTGACCCTGTTCCCCCCCAGCAGCGAGGAGCTGCAGGCCAACAAGGCCACCCTGGTGTGCCTGATCAGCGACTTCTACCCAGGCGCCGTGACCGTGGCCTGGAAGGCCGACAGCAGCCCCGTGAAGGCCGGCGTGGAGACCACCACCCCCAGCAAGCAGAGCAACAACAAGTACGCCGCCAGCAGCTACCTGAGCCTGACCCCCGAGCAGTGGAAGAGCCACAGGTCCTACAGCTGCCAGGTGACCCACGAGGGCAGCACCGTGGAAAAGACCGTGGCCCCAACCGAGTGC AGC

Binding/Reversal Agents

In specific aspects, provided herein are reversal or binding agents,such as inactive FXI/FXIa-derived polypeptide or protein fragments andanti-idiotype antibodies and fragments thereof, which specifically binda target antibody that binds human Factor XI (“FXI”) and/or Factor XIa(“FXIa”) (“anti-FXI/FXIa antibody”). In particular aspects, suchreversal or binding agents inhibit an anticoagulant activity of thetarget antibody. In a specific aspect, such reversal or binding agentsblock the target antibody from binding to human FXI and/or FXIa. In aspecific aspect, such reversal or binding agents (e.g., anti-idiotypeantibodies and fragments thereof) bind to the antigen-binding region ofthe target anti-FXI/FXIa antibody and block the target antibody frombinding to human FXI and/or FXIa.

In a specific aspect, provided herein is a reversal or binding agentwhich is an inactive FXI/FXIa-derived polypeptide or protein fragmentthat specifically binds to a target anti-FXI/FXIa antibody (e.g., anantibody described in Table 1), and is capable of inhibiting ananticoagulant activity of the target antibody and/or is capable ofblocking the target antibody from binding to human FXI and/or FXIa. Theactivity of a human FXI/FXIa-derived polypeptide or protein fragment canbe determined using methods described in the art, for example,biochemical assays detecting the cleavage of a fluorescently labeledpeptide, which can be cleaved by FXIa (e.g., fluorescently labeledpeptide with the sequence D-Leu-Pro-Arg*Rh110-D-Pro (product numberBS-2494; Biosyntan GmbH, Berlin, Germany), where “*” indicates thescissile bond, D-Leu: D-leucine, Pro: proline, Arg: arginine, Rh110:rhodamine 110, D-Pro: D-proline). In a particular aspect, a reversal orbinding agent which is an inactive FXI/FXIa-derived polypeptide orprotein fragment comprises or consists essentially of an incompletefragment of the catalytic domain of human FXI, and comprises one or moreof the following amino acid residues of human FXI: Pro410, Arg413,Leu415, Cys416, His431, Cys432, Tyr434, Gly435, Glu437, Tyr472, Lys473,Met474, Ala475, Glu476, Tyr521, Arg522, Lys523, Leu524, Arg525, Asp526,Lys527, Arg548, His552, Ser575, Ser594, Trp595, Gly596, Glu597, Arg602,Glu603, and Arg604. In a particular aspect, a reversal or binding agentwhich is an inactive FXI/FXIa-derived polypeptide or protein fragmentcomprises or consists essentially of a fragment from amino acid residue400, 401, 402, 403, 404, or 405 up to amino acid residue 600, 601, 602,603, 604, or 605, of human FXI (e.g., SEQ ID NO: 1), or fragmentsthereof with approximately 100-150 amino acid residues thereof. In aspecific aspect, In a particular aspect, a reversal or binding agentwhich is an inactive FXI/FXIa-derived polypeptide or protein fragmentdescribed herein comprises one or more mutations rendering the fragmentinactive, for example, as measured by biochemical assays detecting thecleavage of a fluorescently labeled peptide. Other non-limiting examplesof variants of FXIa which can be used as a reversal agent are describedin PCT International Publication No. WO2017/015558.

In one aspect, the present disclosure relates to a reversal or bindingagent (e.g., anti-idiotype antibody and fragments thereof, for example aFab fragment) which specifically binds a target antibody that bindshuman Factor XI (“FXI”) and/or Factor XIa (“FXIa”) (“anti-FXI/FXIaantibody”), for example an anti-FXI/FXIa antibody described in Table 1,such as antibody NOV1401, or affinity matured variants thereof, such asantibody AM1, AM2, AM3, or AM4. In a particular aspect, provided hereinis a binding agent which specifically binds a target antibody that bindshuman Factor XI (“FXI”) and/or Factor XIa (“FXIa”) (“anti-FXI/FXIaantibody”, such as antibody NOV1401) within the catalytic domain,wherein the binding agent inhibits an anticoagulant activity of thetarget antibody, wherein the binding agent binds to the target antibodywith a dissociation constant (K_(D)) of 1 nM or less, and wherein thebinding agent is capable of inhibiting the ability of the targetantibody to delay activated partial thromboplastin time (aPTT) by atleast 35%. In further specific aspects, the binding agent is capable ofinhibiting the ability of the target antibody to delay activated partialthromboplastin time (aPTT) by at least 40%. In further specific aspects,the binding agent is capable of inhibiting the ability of the targetantibody to delay activated partial thromboplastin time (aPTT) by atleast 50%. In further specific aspects, the binding agent is capable ofinhibiting the ability of the target antibody to delay activated partialthromboplastin time (aPTT) by at least 60%. In further specific aspects,the binding agent is capable of inhibiting the ability of the targetantibody to delay activated partial thromboplastin time (aPTT) by atleast 70%. Methods for determining aPTT and delay to aPTT have beendescribed in the art, and are also described herein, e.g., ExamplesSection.

In specific aspects, provided herein are binding agents which inhibit orreverses an anticoagulant activity of a target anti-FXI/FXIa antibody(e.g., NOV1401), wherein the binding agents are antigen-binding humanantibody fragments such as human Fabs. In particular aspects, providedherein are binding agents which inhibit or reverses an anticoagulantactivity of a target anti-FXI/FXIa antibody (e.g., NOV1401), wherein thebinding agents are human anti-idiotype Fabs. In particular aspects,provided herein are binding agents which inhibit or reverses ananticoagulant activity of a target anti-FXI/FXIa antibody (e.g.,NOV1401), wherein the binding agents are human IgG1, IgG2, or IgG4antibodies, or variants thereof.

In further specific aspects, provided herein is a binding agent (e.g.,anti-idiotype antibody) which specifically binds a target anti-FXI/FXIaantibody, wherein the binding agent inhibits an anticoagulant activityof the target anti-FXI/FXIa antibody, and wherein the targetanti-FXI/FXIa antibody comprises (i) a heavy chain variable region (VH)comprising the amino acid sequence of SEQ ID NO: 12 and a light chainvariable region (VL) comprising the amino acid sequence of SEQ ID NO:23; or (ii) a heavy chain comprising the amino acid sequence of SEQ IDNO: 14 and a light chain comprising the amino acid sequence of SEQ IDNO: 25.

In further specific aspects, provided herein is a binding agent (e.g.,anti-idiotype antibody) which specifically binds a target anti-FXI/FXIaantibody, wherein the binding agent inhibits an anticoagulant activityof the target anti-FXI/FXIa antibody, and wherein the targetanti-FXI/FXIa antibody comprises (i) a heavy chain variable region (VH)comprising an amino acid sequence that is at least 90% or 95% identicalto the amino acid sequence of SEQ ID NO: 12 and a light chain variableregion (VL) comprising an amino acid sequence that is at least 90% or95% identical to the amino acid sequence of SEQ ID NO: 23; or (ii) aheavy chain comprising an amino acid sequence that is at least 90% or95% identical to the amino acid sequence of SEQ ID NO: 14 and a lightchain comprising an amino acid sequence that is at least 90% or 95%identical to the amino acid sequence of SEQ ID NO: 25.

In further specific aspects, provided herein is a binding agent (e.g.,anti-idiotype antibody) which specifically binds a target anti-FXI/FXIaantibody, wherein the binding agent inhibits an anticoagulant activityof the target anti-FXI/FXIa antibody, and wherein the targetanti-FXI/FXIa antibody comprises comprises (i) a VH comprisingcomplementarity determining regions HCDR1, HCDR2 and HCDR3 of a VHcomprising the amino acid sequence of SEQ ID NO: 12 and (ii) a VLcomprising complementarity determining regions LCDR1, LCDR2, and LCDR3of a VL comprising the amino acid sequence of SEQ ID NO: 23.

In further specific aspects, provided herein is a binding agent (e.g.,anti-idiotype antibody) which specifically binds a target anti-FXI/FXIaantibody, wherein the binding agent inhibits an anticoagulant activityof the target anti-FXI/FXIa antibody, and wherein the targetanti-FXI/FXIa antibody comprises:

-   -   (A)(i) a VH comprising complementarity determining regions        HCDR1, HCDR2 and HCDR3 comprising the amino acid sequences of        SEQ ID NO: 3, SEQ ID NO: 4, and SEQ ID NO: 5, respectively;        and (ii) a VL comprising complementarity determining regions        LCDR1, LCDR2, and LCDR3 comprising the amino acid sequence of        SEQ ID NO: 16, SEQ ID NO: 17, and SEQ ID NO: 18, respectively;    -   (B)(i) a VH comprising complementarity determining regions        HCDR1, HCDR2 and HCDR3 comprising the amino acid sequences of        SEQ ID NO: 6, SEQ ID NO: 4, and SEQ ID NO: 5, respectively;        and (ii) a VL comprising complementarity determining regions        LCDR1, LCDR2, and LCDR3 comprising the amino acid sequence of        SEQ ID NO: 16, SEQ ID NO: 17, and SEQ ID NO: 18, respectively;    -   (C)(i) a VH comprising complementarity determining regions        HCDR1, HCDR2 and HCDR3 comprising the amino acid sequences of        SEQ ID NO: 7, SEQ ID NO: 8, and SEQ ID NO: 5, respectively;        and (ii) a VL comprising complementarity determining regions        LCDR1, LCDR2, and LCDR3 comprising the amino acid sequence of        SEQ ID NO: 19, SEQ ID NO: 20, and SEQ ID NO: 21, respectively;        or    -   (D)(i) a VH comprising complementarity determining regions        HCDR1, HCDR2 and HCDR3 comprising the amino acid sequences of        SEQ ID NO: 9, SEQ ID NO: 10, and SEQ ID NO: 11, respectively;        and (ii) a VL comprising complementarity determining regions        LCDR1, LCDR2, and LCDR3 comprising the amino acid sequence of        SEQ ID NO: 22, SEQ ID NO: 20, and SEQ ID NO: 18, respectively;

In further specific aspects, provided herein is a binding agent (e.g.,anti-idiotype antibody) which specifically binds a target anti-FXI/FXIaantibody, wherein the binding agent inhibits an anticoagulant activityof the target anti-FXI/FXIa antibody, and wherein the targetanti-FXI/FXIa antibody competes, for binding to FXI/FXIa, with anotheranti-FXI/FXIa antibody (e.g., antibody NOV1401) comprising a heavy chaincomprising the amino acid sequence of SEQ ID NO: 14 and a light chaincomprising the amino acid sequence of SEQ ID NO: 25.

In further specific aspects, provided herein is a binding agent (e.g.,anti-idiotype antibody) which specifically binds a target anti-FXI/FXIaantibody, wherein the binding agent inhibits an anticoagulant activityof the target anti-FXI/FXIa antibody, and wherein the targetanti-FXI/FXIa antibody binds the same epitope as another anti-FXI/FXIaantibody (e.g., antibody NOV1401) comprising a heavy chain comprisingthe amino acid sequence of SEQ ID NO: 14 and a light chain comprisingthe amino acid sequence of SEQ ID NO: 25.

In further specific aspects, provided herein is a binding agent (e.g.,anti-idiotype antibody) which specifically binds a target anti-FXI/FXIaantibody, wherein the binding agent inhibits an anticoagulant activityof the target anti-FXI/FXIa antibody, and wherein the targetanti-FXI/FXIa antibody binds an epitope of human FXI and/or FXIacomprising one, two, three, four, five, six, seven, eight, nine, ten,eleven, twelve, thirteen, fourteen, fifteen or more, or all of, aminoacid residues selected from: Pro410, Arg413, Leu415, Cys416, His431,Cys432, Tyr434, Gly435, Glu437, Tyr472, Lys473, Met474, Ala475, Glu476,Tyr521, Arg522, Lys523, Leu524, Arg525, Asp526, Lys527, Arg548, His552,Ser575, Ser594, Trp595, Gly596, Glu597, Arg602, Glu603, and Arg604. Inparticular aspects, provided herein is a binding agent (e.g.,anti-idiotype antibody) which specifically binds a target anti-FXI/FXIaantibody, wherein the binding agent inhibits an anticoagulant activityof the target anti-FXI/FXIa antibody, and wherein the targetanti-FXI/FXIa antibody contacts one, two, three, four, five, six, seven,eight, nine, ten, eleven, twelve, thirteen, fourteen, fifteen or more,or all of, amino acid residues of human FXI selected from: Pro410,Arg413, Leu415, Cys416, His431, Cys432, Tyr434, Gly435, Glu437, Tyr472,Lys473, Met474, Ala475, Glu476, Tyr521, Arg522, Lys523, Leu524, Arg525,Asp526, Lys527, Arg548, His552, Ser575, Ser594, Trp595, Gly596, Glu597,Arg602, Glu603, and Arg604. In specific aspects, reversal binding agentsprovided herein (e.g., human anti-idiotype antibodies) bind to ananti-FXI/FXIa antibody which is NOV1401 or competes for binding withNOV1401 to human FXI/FXIa and which anti-FXI/FXIa antibody does notcontact amino acid residue Asp480 of human FXI/FXIa. In specificaspects, reversal binding agents provided herein (e.g., humananti-idiotype antibodies) bind to an anti-FXI/FXIa antibody which isNOV1401 or competes for binding with NOV1401 to human FXI/FXIa and whichanti-FXI/FXIa antibody does not contact one or more amino acid residuesselected from: His414, Ser477, Asp480, Lys572, Asp569, and Gly598 ofhuman FXI/FXIa. In specific aspects, reversal binding agents providedherein (e.g., human anti-idiotype antibodies) bind to an anti-FXI/FXIaantibody which is NOV1401 or competes for binding with NOV1401 to humanFXI/FXIa and which anti-FXI/FXIa antibody contacts one, two, three,four, five, six, seven, eight, or more, or all, of amino acid residuesLeu415, Cys416, His431, Cys432, Gly435, Glu437, Tyr472, Lys473, Glu476,Arg548, His552, Ser575, Trp595, Gly596, Glu597, Arg602, Glu603, andArg604 of human FXI/FXIa. In specific aspects, reversal binding agentsprovided herein (e.g., human anti-idiotype antibodies) bind to ananti-FXI/FXIa antibody which contacts amino acid residues His431 andSer575 of human FXI/FXIa. In specific aspects, a reversal binding agentprovided herein, which binds to an anti-FXI/FXIa antibody (e.g.,NOV1401), is not antibody C4 (anti-idiotype antibody targetinganti-FXI/FXIa antibody DEF as described in PCT International PublicationNo. WO2017/015619).

In specific aspects, provided herein are reversal binding agents (e.g.,anti-idiotype antibodies and fragment thereof such as Fabs) that bind tothe antigen-binding region of NOV1401, and contacts one or more of theresidues in light chain and heavy chain of NOV1401 forming the paratope.In specific aspects, a reversal binding agent agent (e.g., anti-idiotypeantibody and fragment thereof such as a Fab) provided herein binds toNOV1401 within the antigen-binding region, and contacts one, two, three,four, five six, seven, eight, nine, or more, or all, of the followingresidues in the light chain of NOV1401: Ser27, Gly30, Ser31, Asn32,Asp33, Tyr50, Lys51, Tyr53, Asn54, Lys67, Trp92, Gln94, Arg95, Phe97,Asp98, and Val99 (residues are numbered with reference to SEQ ID NO:25). In specific aspects, a reversal binding agent agent (e.g.,anti-idiotype antibody and fragment thereof such as a Fab) providedherein binds to NOV1401 within the antigen-binding region, and contactsone, two, three, four, five six, seven, eight, nine, or more, or all, ofthe following residues in the heavy chain of NOV1401 contact humanFXI/FXIa: Phe27, Thr28, Ser30, Thr31, Ala33, Trp47, Ser52, Tyr59, Tyr60,Glu99, Ser101, Tyr102, Leu103, Tyr104, and Ser105 (residues are numberedwith reference to SEQ ID NO: 14). In specific aspects, a reversalbinding agent agent (e.g., anti-idiotype antibody and fragment thereofsuch as a Fab) provided herein binds to NOV1401 within theantigen-binding region, and contacts one, two, three, four, five six,seven, eight, nine, ten or more amino acid residues selected from thefollowing in light chain and/or the heavy chain of NOV1401 forming theparatope: (i) Ser27, Gly30, Ser31, Asn32, Asp33, Tyr50, Lys51, Tyr53,Asn54, Lys67, Trp92, Gln94, Arg95, Phe97, Asp98, and Val99 in the lightchain of NOV1401 (residues are numbered with reference to SEQ ID NO:25); and (ii) Phe27, Thr28, Ser30, Thr31, Ala33, Trp47, Ser52, Tyr59,Tyr60, Glu99, Ser101, Tyr102, Leu103, Tyr104, and Ser105 in the heavychain of NOV1401 (residues are numbered with reference to SEQ ID NO:14).

In particular aspects, anti-FXI/FXIa antibody binding agents providedherein is capable of reducing, inhibiting, or reversing (e.g., partiallyreversing) one or more of the following anticoagulant effects mediatedby an anti-FXI/FXIa antibody: (i) aPTT prolongation in aPTT assays and(ii) reduction in the amount of thrombin in a thrombin generation assay(TGA) in human plasma. Protocols and assays to measure theseanticoagulant activities have been described, and exemplary assays aredescribed herein, e.g., in the Examples Section.

In a specific aspect, an anti-FXI/FXIa antibody binding agent providedherein is capable reversing anticoagulant effects of a target FXI/FXIaantibody as characterized by reducing, inhibiting, or reversing aPTTprolongation by an anti-FXI/FXIa antibody (e.g., NOV1401) by at least10%, at least 20%, at least 30%, at least 40%, at least 50%, at least60%, at least 70%, at least 80%, or at least 90%, as determined by anaPTT assay, described in the art or herein.

In a specific aspect, an anti-FXI/FXIa antibody binding agent providedherein is capable reversing anticoagulant effects of a target FXI/FXIaantibody as characterized by reducing, inhibiting, or reversingreduction in the amount of thrombin in a thrombin generation assay (TGA)in human plasma by an anti-FXI/FXIa antibody (e.g., NOV1401) by at least10%, at least 20%, at least 30%, at least 40%, at least 50%, at least60%, at least 70%, at least 80%, or at least 90%.

In further specific aspects, provided herein is a binding agent (e.g.,anti-idiotype antibody) which specifically binds a target anti-FXI/FXIaantibody, wherein the binding agent inhibits an anticoagulant activityof the target anti-FXI/FXIa antibody, wherein the target anti-FXI/FXIaantibody comprises (i) a heavy chain variable region (VH) comprising theamino acid sequence of SEQ ID NO: 12 and a light chain variable region(VL) comprising the amino acid sequence of SEQ ID NO: 23; or (ii) aheavy chain comprising the amino acid sequence of SEQ ID NO: 14 and alight chain comprising the amino acid sequence of SEQ ID NO: 25, andwherein the binding agent is an antibody or antigen-binding fragmentthereof comprising (1) a VH comprising complementarity determiningregions HCDR1, HCDR2, and HCDR3 selected from those set forth in Table2, and (2) a VL comprising complementarity determining regions LCDR1,LCDR2, and LCDR3 selected from those set forth in Table 2. In aparticular aspect, the binding agent (e.g., anti-idiotype antibody)comprises Combined HCDR1, HCDR2, and HCDR3 selected from those set forthin Table 2 and Combined LCDR1, LCDR2, and LCDR3 selected from those setforth in Table 2. In a particular aspect, the binding agent (e.g.,anti-idiotype antibody) comprises Kabat HCDR1, HCDR2, and HCDR3 selectedfrom those set forth in Table 2 and Kabat LCDR1, LCDR2, and LCDR3selected from those set forth in Table 2. In a particular aspect, thebinding agent (e.g., anti-idiotype antibody) comprises Chothia HCDR1,HCDR2, and HCDR3 selected from those set forth in Table 2 and ChothiaLCDR1, LCDR2, and LCDR3 selected from those set forth in Table 2. In aparticular aspect, the binding agent (e.g., anti-idiotype antibody)comprises IMGT HCDR1, HCDR2, and HCDR3 selected from those set forth inTable 2 and IMGT LCDR1, LCDR2, and LCDR3 selected from those set forthin Table 2.

TABLE 2 Examples of anti-FXI/FXIa Antibody Binding Agents(e.g., anti-idiotype antibody and Fab fragments descriptionDNA or amino acid sequence IDT1 SEQ ID NO: 27 HCDR1 GFTFSDYAMS(Combined) SEQ ID NO: 28 HCDR2 VIDYSSSNTYYADSVKG (Combined)SEQ ID NO: 29 HCDR3 EGYSYRSIRFDY (Combined) SEQ ID NO: 30 HCDR1 DYAMS(Kabat) SEQ ID NO: 31 HCDR2 VIDYSSSNTYYADSVKG (Kabat) SEQ ID NO: 32HCDR3 EGYSYRSIRFDY (Kabat) SEQ ID NO: 33 HCDR1 GFTFSDY (Chothia)SEQ ID NO: 34 HCDR2 DYSSSN (Chothia) SEQ ID NO: 35 HCDR3 EGYSYRSIRFDY(Chothia) SEQ ID NO: 36 HCDR1 GFTFSDYA (IMGT) SEQ ID NO: 37 HCDR2IDYSSSNT (IMGT) SEQ ID NO: 38 HCDR3 AREGYSYRSIRFDY (IMGT) SEQ ID NO: 39VH QVQLLESGGGLVQPGGSLRLSCAASGFTFSDYAMSWVRQAPGKGLEWVSVIDYSSSNTYYADSVKGRFTISRDNSKNTLYLQMNSLRAEDTAVYYCAREGYSYRSIRFDYWGQGTLVTVSS SEQ ID NO: 40 DNA VHCAAGTGCAGCTGCTGGAATCTGGCGGCGGACTGGTGCAGCCTGGCGGTAGTCTGAGACTGTCTTGCGCCGCCTCCGGCTTCACCTTCTCCGACTACGCCATGTCCTGGGTCCGACAGGCCCCTGGCAAGGGCCTGGAGTGGGTGTCCGTGATCGACTACTCCTCCTCCAACACCTACTACGCCGACTCCGTGAAGGGCCGGTTCACCATCTCCCGGGACAACTCCAAGAACACCCTGTACCTGCAGATGAACTCCCTGCGGGCCGAGGACACCGCCGTGTACTACTGCGCCAGAGAGGGCTACTCCTACCGGTCCATCAGATTCGACTACTGGGGCCAGGGCACCCTGGTCA CCGTGTCCTCT SEQ ID NO: 41Heavy QVQLLESGGGLVQPGGSLRLSCAASGFTFSDYAMSWVRQAPGKG ChainLEWVSVIDYSSSNTYYADSVKGRFTISRDNSKNTLYLQMNSLRAEDTAVYYCAREGYSYRSIRFDYWGQGTLVTVSSASTKGPSVFPLAPSSKSTSGGTAALGCLVKDYFPEPVTVSWNSGALTSGVHTFPAVLQSSGLYSLSSVVTVPSSSLGTQTYICNVNHKPSNTKVDKRVE PKSC SEQ ID NO: 42 DNACAAGTGCAGCTGCTGGAATCTGGCGGCGGACTGGTGCAGCCTGG Heavy ChainCGGTAGTCTGAGACTGTCTTGCGCCGCCTCCGGCTTCACCTTCTCCGACTACGCCATGTCCTGGGTCCGACAGGCCCCTGGCAAGGGCCTGGAGTGGGTGTCCGTGATCGACTACTCCTCCTCCAACACCTACTACGCCGACTCCGTGAAGGGCCGGTTCACCATCTCCCGGGACAACTCCAAGAACACCCTGTACCTGCAGATGAACTCCCTGCGGGCCGAGGACACCGCCGTGTACTACTGCGCCAGAGAGGGCTACTCCTACCGGTCCATCAGATTCGACTACTGGGGCCAGGGCACCCTGGTCACCGTGTCCTCTGCTAGCACCAAGGGCCCCTCCGTGTTCCCTCTGGCCCCTTCCAGCAAGTCTACCTCTGGCGGCACCGCTGCTCTGGGCTGCCTGGTGAAGGACTACTTCCCTGAGCCTGTGACAGTGTCCTGGAACTCTGGCGCCCTGACCTCCGGCGTGCACACCTTCCCTGCCGTGCTGCAGTCCTCCGGCCTGTACTCCCTGTCCTCCGTGGTGACAGTGCCTTCCTCCAGCCTGGGCACCCAGACCTATATCTGCAACGTGAACCACAAGCCTTCCAACACCAAGGTGGACAAGCGGGTGGAG CCTAAGTCATGC SEQ ID NO: 43LCDR1 RASQSISSNLN (Combined) SEQ ID NO: 44 LCDR2 AASNLQS (Combined)SEQ ID NO: 45 LCDR3 LQFDHTPFT (Combined) SEQ ID NO: 46 LCDR1 RASQSISSNLN(Kabat) SEQ ID NO: 47 LCDR2 AASNLQS (Kabat) SEQ ID NO: 48 LCDR3LQFDHTPFT (Kabat) SEQ ID NO: 49 LCDR1 SQSISSN (Chothia) SEQ ID NO: 50LCDR2 AAS (Chothia) SEQ ID NO: 51 LCDR3 FDHTPF (Chothia) SEQ ID NO: 52LCDR1 QSISSN (IMGT) SEQ ID NO: 53 LCDR2 AS (IMGT) SEQ ID NO: 54 LCDR3LQFDHTPFT (IMGT) SEQ ID NO: 55 VLDIQMTQSPSSLSASVGDRVTITCRASQSISSNLNWYQQKPGKAPKLLIYAASNLQSGVPSRFSGSGSGTDFTLTISSLQPEDFATYYC LQFDHTPFTFGQGTKVEIKSEQ ID NO: 56 DNA VL GACATCCAGATGACCCAGAGCCCCTCCAGCCTGTCCGCCTCCGTGGGCGACAGAGTGACCATCACCTGTCGGGCCTCCCAGTCCATCTCCTCCAACCTGAACTGGTATCAGCAGAAGCCCGGCAAGGCCCCTAAGCTGCTGATCTACGCCGCCAGCAACCTGCAGTCCGGCGTGCCCTCCAGATTCTCCGGCTCTGGCTCCGGCACCGACTTCACCCTGACCATCTCCAGCCTGCAGCCCGAGGACTTCGCCACCTACTACTGCCTGCAGTTCGACCACACCCCTTTCACCTTCGGCCAGGGCACCAA AGTGGAAATCAAG SEQ ID NO: 57Light DIQMTQSPSSLSASVGDRVTITCRASQSISSNLNWYQQKPGKAP ChainKLLIYAASNLQSGVPSRFSGSGSGTDFTLTISSLQPEDFATYYCLQFDHTPFTFGQGTKVEIKRTVAAPSVFIFPPSDEQLKSGTASVVCLLNNFYPREAKVQWKVDNALQSGNSQESVTEQDSKDSTYSLSSTLTLSKADYEKHKVYACEVTHQGLSSPVTKSFNRGEC SEQ ID NO: 58 DNAGACATCCAGATGACCCAGAGCCCCTCCAGCCTGTCCGCCTCCGT LightGGGCGACAGAGTGACCATCACCTGTCGGGCCTCCCAGTCCATCT ChainCCTCCAACCTGAACTGGTATCAGCAGAAGCCCGGCAAGGCCCCTAAGCTGCTGATCTACGCCGCCAGCAACCTGCAGTCCGGCGTGCCCTCCAGATTCTCCGGCTCTGGCTCCGGCACCGACTTCACCCTGACCATCTCCAGCCTGCAGCCCGAGGACTTCGCCACCTACTACTGCCTGCAGTTCGACCACACCCCTTTCACCTTCGGCCAGGGCACCAAAGTGGAAATCAAGCGTACGGTGGCCGCTCCCAGCGTGTTCATCTTCCCCCCCAGCGACGAGCAGCTGAAGAGCGGCACCGCCAGCGTGGTGTGCCTGCTGAACAACTTCTACCCCCGGGAGGCCAAGGTGCAGTGGAAGGTGGACAACGCCCTGCAGAGCGGCAACAGCCAGGAGAGCGTCACCGAGCAGGACAGCAAGGACTCCACCTACAGCCTGAGCAGCACCCTGACCCTGAGCAAGGCCGACTACGAGAAGCATAAGGTGTACGCCTGCGAGGTGACCCACCAGGGCCTGTCCAGCCCCGTGA CCAAGAGCTTCAACAGGGGCGAGTGCIDT2 SEQ ID NO: 59 HCDR1 GFTFSSAAVH (Combined) SEQ ID NO: 60 HCDR2RIKSKADGGTTDYAAPVKG (Combined) SEQ ID NO: 61 HCDR3 DSPSISSYSIPYFSGMDV(Combined) SEQ ID NO: 62 HCDR1 SAAVH (Kabat) SEQ ID NO: 63 HCDR2RIKSKADGGTTDYAAPVKG (Kabat) SEQ ID NO: 64 HCDR3 DSPSISSYSIPYFSGMDV(Kabat) SEQ ID NO: 65 HCDR1 GFTFSSA (Chothia) SEQ ID NO: 66 HCDR2KSKADGGT (Chothia) SEQ ID NO: 67 HCDR3 DSPSISSYSIPYFSGMDV (Chothia)SEQ ID NO: 68 HCDR1 GFTFSSAA (IMGT) SEQ ID NO: 69 HCDR2 IKSKADGGTT(IMGT) SEQ ID NO: 70 HCDR3 ARDSPSISSYSIPYFSGMDV (IMGT) SEQ ID NO: 71 VHQVQLVESGGGLVKPGGSLRLSCAASGFTFSSAAVHWVRQAPGKGLEWVGRIKSKADGGTTDYAAPVKGRFTISRDDSKNTLYLQMNSLKTEDTAVYYCARDSPSISSYSIPYFSGMDVWGQGTLVTVSS SEQ ID NO: 72 DNA VHCAAGTGCAGCTGGTGGAATCTGGCGGCGGACTGGTCAAGCCTGGCGGTAGCCTGAGACTGTCTTGCGCCGCCTCCGGCTTCACCTTCTCCTCTGCCGCTGTGCACTGGGTCCGACAGGCCCCTGGCAAGGGCCTGGAGTGGGTCGGACGGATCAAGTCCAAGGCCGACGGCGGCACCACCGACTACGCTGCCCCTGTGAAGGGCCGGTTCACCATCTCCCGGGACGACTCCAAGAACACCCTGTACCTGCAGATGAACTCCCTGAAAACCGAGGACACCGCCGTGTACTACTGCGCCAGAGACTCCCCATCTATCTCCAGCTACTCCATCCCCTACTTCTCCGGCATGGACGTGTGGGGCCAGGGCACCCTGGTCACCGTGTCCTCT SEQ ID NO: 73 HeavyQVQLVESGGGLVKPGGSLRLSCAASGFTFSSAAVHWVRQAPGKG ChainLEWVGRIKSKADGGTTDYAAPVKGRFTISRDDSKNTLYLQMNSLKTEDTAVYYCARDSPSISSYSIPYFSGMDVWGQGTLVTVSSASTKGPSVFPLAPSSKSTSGGTAALGCLVKDYFPEPVTVSWNSGALTSGVHTFPAVLQSSGLYSLSSVVTVPSSSLGTQTYICNVNHKPSN TKVDKRVEPKSC SEQ ID NO: 74DNA CAAGTGCAGCTGGTGGAATCTGGCGGCGGACTGGTCAAGCCTGG HeavyCGGTAGCCTGAGACTGTCTTGCGCCGCCTCCGGCTTCACCTTCT ChainCCTCTGCCGCTGTGCACTGGGTCCGACAGGCCCCTGGCAAGGGCCTGGAGTGGGTCGGACGGATCAAGTCCAAGGCCGACGGCGGCACCACCGACTACGCTGCCCCTGTGAAGGGCCGGTTCACCATCTCCCGGGACGACTCCAAGAACACCCTGTACCTGCAGATGAACTCCCTGAAAACCGAGGACACCGCCGTGTACTACTGCGCCAGAGACTCCCCATCTATCTCCAGCTACTCCATCCCCTACTTCTCCGGCATGGACGTGTGGGGCCAGGGCACCCTGGTCACCGTGTCCTCTGCTAGCACCAAGGGCCCCTCCGTGTTCCCTCTGGCCCCTTCCAGCAAGTCTACCTCTGGCGGCACCGCTGCTCTGGGCTGCCTGGTGAAGGACTACTTCCCTGAGCCTGTGACAGTGTCCTGGAACTCTGGCGCCCTGACCTCCGGCGTGCACACCTTCCCTGCCGTGCTGCAGTCCTCCGGCCTGTACTCCCTGTCCTCCGTGGTGACAGTGCCTTCCTCCAGCCTGGGCACCCAGACCTATATCTGCAACGTGAACCACAAGCCTTCCAACACCAAGGTGGACAAGCGGGTGGAGCCTAAGTCATGC SEQ ID NO: 75 LCDR1 RASQGIRAWLN(Combined) SEQ ID NO: 76 LCDR2 AASSLQS (Combined) SEQ ID NO: 77 LCDR3HQYITHPPT (Combined) SEQ ID NO: 78 LCDR1 RASQGIRAWLN (Kabat)SEQ ID NO: 79 LCDR2 AASSLQS (Kabat) SEQ ID NO: 80 LCDR3 HQYITHPPT(Kabat) SEQ ID NO: 81 LCDR1 SQGIRAW (Chothia) SEQ ID NO: 82 LCDR2 AAS(Chothia) SEQ ID NO: 83 LCDR3 YITHPP (Chothia) SEQ ID NO: 84 LCDR1QGIRAW (IMGT) SEQ ID NO: 85 LCDR2 AS (IMGT) SEQ ID NO: 86 LCDR3HQYITHPPT (IMGT) SEQ ID NO: 87 VLDIQMTQSPSSLSASVGDRVTITCRASQGIRAWLNWYQQKPGKAPKLLIYAASSLQSGVPSRFSGSGSGTDFTLTISSLQPEDFATYYC HQYITHPPTFGQGTKVEIKSEQ ID NO: 88 DNA VL GACATCCAGATGACCCAGAGCCCCTCCAGCCTGTCCGCCTCCGTGGGCGACAGAGTGACCATCACCTGTCGGGCCTCTCAGGGCATCCGGGCCTGGCTGAACTGGTATCAGCAGAAGCCCGGCAAGGCCCCTAAGCTGCTGATCTACGCCGCCAGCTCCCTGCAGTCCGGCGTGCCCTCCAGATTCTCCGGCTCTGGCTCCGGCACCGACTTCACCCTGACCATCTCCAGCCTGCAGCCCGAGGACTTCGCCACCTACTACTGCCACCAGTACATCACCCACCCTCCCACCTTCGGCCAGGGCACCAA AGTGGAAATCAAG SEQ ID NO: 89Light DIQMTQSPSSLSASVGDRVTITCRASQGIRAWLNWYQQKPGKAP ChainKLLIYAASSLQSGVPSRFSGSGSGTDFTLTISSLQPEDFATYYCHQYITHPPTFGQGTKVEIKRTVAAPSVFIFPPSDEQLKSGTASVVCLLNNFYPREAKVQWKVDNALQSGNSQESVTEQDSKDSTYSLSSTLTLSKADYEKHKVYACEVTHQGLSSPVTKSFNRGEC SEQ ID NO: 90 DNAGACATCCAGATGACCCAGAGCCCCTCCAGCCTGTCCGCCTCCGT LightGGGCGACAGAGTGACCATCACCTGTCGGGCCTCTCAGGGCATCC ChainGGGCCTGGCTGAACTGGTATCAGCAGAAGCCCGGCAAGGCCCCTAAGCTGCTGATCTACGCCGCCAGCTCCCTGCAGTCCGGCGTGCCCTCCAGATTCTCCGGCTCTGGCTCCGGCACCGACTTCACCCTGACCATCTCCAGCCTGCAGCCCGAGGACTTCGCCACCTACTACTGCCACCAGTACATCACCCACCCTCCCACCTTCGGCCAGGGCACCAAAGTGGAAATCAAGCGTACGGTGGCCGCTCCCAGCGTGTTCATCTTCCCCCCCAGCGACGAGCAGCTGAAGAGCGGCACCGCCAGCGTGGTGTGCCTGCTGAACAACTTCTACCCCCGGGAGGCCAAGGTGCAGTGGAAGGTGGACAACGCCCTGCAGAGCGGCAACAGCCAGGAGAGCGTCACCGAGCAGGACAGCAAGGACTCCACCTACAGCCTGAGCAGCACCCTGACCCTGAGCAAGGCCGACTACGAGAAGCATAAGGTGTACGCCTGCGAGGTGACCCACCAGGGCCTGTCCAGCCCCGTGA CCAAGAGCTTCAACAGGGGCGAGTGCIDT3 SEQ ID NO: 91 HCDR1 GFTFQSAAVH (Combined) SEQ ID NO: 92 HCDR2RIKSKADGGTTDYAAPVKG (Combined) SEQ ID NO: 93 HCDR3 DSPSISSYSIPYFSGMDV(Combined) SEQ ID NO: 94 HCDR1 SAAVH (Kabat) SEQ ID NO: 95 HCDR2RIKSKADGGTTDYAAPVKG (Kabat) SEQ ID NO: 96 HCDR3 DSPSISSYSIPYFSGMDV(Kabat) SEQ ID NO: 97 HCDR1 GFTFQSA (Chothia) SEQ ID NO: 98 HCDR2KSKADGGT (Chothia) SEQ ID NO: 99 HCDR3 DSPSISSYSIPYFSGMDV (Chothia)SEQ ID NO: 100 HCDR1 GFTFQSAA (IMGT) SEQ ID NO: 101 HCDR2 IKSKADGGTT(IMGT) SEQ ID NO: 102 HCDR3 ARDSPSISSYSIPYFSGMDV (IMGT) SEQ ID NO: 103VH QVQLVESGGGLVKPGGSLRLSCAASGFTFQSAAVHWVRQAPGKGLEWVGRIKSKADGGTTDYAAPVKGRFTISRDDSKNTLYLQMNSLKTEDTAVYYCARDSPSISSYSIPYFSGMDVWGQGTLVTVSS SEQ ID NO: 104 DNA VHCAAGTGCAGCTGGTGGAATCTGGCGGCGGACTGGTCAAGCCTGGCGGTAGCCTGAGACTGTCTTGCGCCGCCTCCGGCTTCACCTTCCAGTCTGCCGCTGTGCACTGGGTCCGACAGGCCCCTGGCAAGGGCCTGGAGTGGGTCGGACGGATCAAGTCCAAGGCCGACGGCGGCACCACCGACTACGCTGCCCCTGTGAAGGGCCGGTTCACCATCTCCCGGGACGACTCCAAGAACACCCTGTACCTGCAGATGAACTCCCTGAAAACCGAGGACACCGCCGTGTACTACTGCGCCAGAGACTCCCCATCTATCTCCAGCTACTCCATCCCCTACTTCTCCGGCATGGACGTGTGGGGCCAGGGCACCCTGGTCACCGTGTCCTCT SEQ ID NO: 105 HeavyQVQLVESGGGLVKPGGSLRLSCAASGFTFQSAAVHWVRQAPGKG ChainLEWVGRIKSKADGGTTDYAAPVKGRFTISRDDSKNTLYLQMNSLKTEDTAVYYCARDSPSISSYSIPYFSGMDVWGQGTLVTVSSASTKGPSVFPLAPSSKSTSGGTAALGCLVKDYFPEPVTVSWNSGALTSGVHTFPAVLQSSGLYSLSSVVTVPSSSLGTQTYICNVNHKPSN TKVDKRVEPKSC SEQ ID NO: 106DNA CAAGTGCAGCTGGTGGAATCTGGCGGCGGACTGGTCAAGCCTGG HeavyCGGTAGCCTGAGACTGTCTTGCGCCGCCTCCGGCTTCACCTTCC ChainAGTCTGCCGCTGTGCACTGGGTCCGACAGGCCCCTGGCAAGGGCCTGGAGTGGGTCGGACGGATCAAGTCCAAGGCCGACGGCGGCACCACCGACTACGCTGCCCCTGTGAAGGGCCGGTTCACCATCTCCCGGGACGACTCCAAGAACACCCTGTACCTGCAGATGAACTCCCTGAAAACCGAGGACACCGCCGTGTACTACTGCGCCAGAGACTCCCCATCTATCTCCAGCTACTCCATCCCCTACTTCTCCGGCATGGACGTGTGGGGCCAGGGCACCCTGGTCACCGTGTCCTCTGCTAGCACCAAGGGCCCCTCCGTGTTCCCTCTGGCCCCTTCCAGCAAGTCTACCTCTGGCGGCACCGCTGCTCTGGGCTGCCTGGTGAAGGACTACTTCCCTGAGCCTGTGACAGTGTCCTGGAACTCTGGCGCCCTGACCTCCGGCGTGCACACCTTCCCTGCCGTGCTGCAGTCCTCCGGCCTGTACTCCCTGTCCTCCGTGGTGACAGTGCCTTCCTCCAGCCTGGGCACCCAGACCTATATCTGCAACGTGAACCACAAGCCTTCCAACACCAAGGTGGACAAGCGGGTGGAGCCTAAGTCATGC SEQ ID NO: 107 LCDR1 RASQGIRAWLN(Combined) SEQ ID NO: 108 LCDR2 AASSLQS (Combined) SEQ ID NO: 109 LCDR3HQYITHPPT (Combined) SEQ ID NO: 110 LCDR1 RASQGIRAWLN (Kabat)SEQ ID NO: 111 LCDR2 AASSLQS (Kabat) SEQ ID NO: 112 LCDR3 HQYITHPPT(Kabat) SEQ ID NO: 113 LCDR1 SQGIRAW (Chothia) SEQ ID NO: 114 LCDR2 AAS(Chothia) SEQ ID NO: 115 LCDR3 YITHPP (Chothia) SEQ ID NO: 116 LCDR1QGIRAW (IMGT) SEQ ID NO: 117 LCDR2 AS (IMGT) SEQ ID NO: 118 LCDR3HQYITHPPT (IMGT) SEQ ID NO: 119 VLDIQMTQSPSSLSASVGDRVTITCRASQGIRAWLNWYQQKPGKAPKLLIYAASSLQSGVPSRFSGSGSGTDFTLTISSLQPEDFATYYC HQYITHPPTFGQGTKVEIKSEQ ID NO: 120 DNA VL GACATCCAGATGACCCAGAGCCCCTCCAGCCTGTCCGCCTCCGTGGGCGACAGAGTGACCATCACCTGTCGGGCCTCTCAGGGCATCCGGGCCTGGCTGAACTGGTATCAGCAGAAGCCCGGCAAGGCCCCTAAGCTGCTGATCTACGCCGCCAGCTCCCTGCAGTCCGGCGTGCCCTCCAGATTCTCCGGCTCTGGCTCCGGCACCGACTTCACCCTGACCATCTCCAGCCTGCAGCCCGAGGACTTCGCCACCTACTACTGCCACCAGTACATCACCCACCCTCCCACCTTCGGCCAGGGCACCAA AGTGGAAATCAAGSEQ ID NO: 121 Light DIQMTQSPSSLSASVGDRVTITCRASQGIRAWLNWYQQKPGKAP ChainKLLIYAASSLQSGVPSRFSGSGSGTDFTLTISSLQPEDFATYYCHQYITHPPTFGQGTKVEIKRTVAAPSVFIFPPSDEQLKSGTASVVCLLNNFYPREAKVQWKVDNALQSGNSQESVTEQDSKDSTYSLSSTLTLSKADYEKHKVYACEVTHQGLSSPVTKSFNRGEC SEQ ID NO: 122 DNAGACATCCAGATGACCCAGAGCCCCTCCAGCCTGTCCGCCTCCGT LightGGGCGACAGAGTGACCATCACCTGTCGGGCCTCTCAGGGCATCC ChainGGGCCTGGCTGAACTGGTATCAGCAGAAGCCCGGCAAGGCCCCTAAGCTGCTGATCTACGCCGCCAGCTCCCTGCAGTCCGGCGTGCCCTCCAGATTCTCCGGCTCTGGCTCCGGCACCGACTTCACCCTGACCATCTCCAGCCTGCAGCCCGAGGACTTCGCCACCTACTACTGCCACCAGTACATCACCCACCCTCCCACCTTCGGCCAGGGCACCAAAGTGGAAATCAAGCGTACGGTGGCCGCTCCCAGCGTGTTCATCTTCCCCCCCAGCGACGAGCAGCTGAAGAGCGGCACCGCCAGCGTGGTGTGCCTGCTGAACAACTTCTACCCCCGGGAGGCCAAGGTGCAGTGGAAGGTGGACAACGCCCTGCAGAGCGGCAACAGCCAGGAGAGCGTCACCGAGCAGGACAGCAAGGACTCCACCTACAGCCTGAGCAGCACCCTGACCCTGAGCAAGGCCGACTACGAGAAGCATAAGGTGTACGCCTGCGAGGTGACCCACCAGGGCCTGTCCAGCCCCGTGA CCAAGAGCTTCAACAGGGGCGAGTGCIDT4 SEQ ID NO: 123 HCDR1 GFTFSSAAVH (Combined) SEQ ID NO: 124 HCDR2RIKSKASGGTTDYAAPVKG (Combined) SEQ ID NO: 125 HCDR3 DSPSISSYSIPYFSGMDV(Combined) SEQ ID NO: 126 HCDR1 SAAVH (Kabat) SEQ ID NO: 127 HCDR2RIKSKASGGTTDYAAPVKG (Kabat) SEQ ID NO: 128 HCDR3 DSPSISSYSIPYFSGMDV(Kabat) SEQ ID NO: 129 HCDR1 GFTFSSA (Chothia) SEQ ID NO: 130 HCDR2KSKASGGT (Chothia) SEQ ID NO: 131 HCDR3 DSPSISSYSIPYFSGMDV (Chothia)SEQ ID NO: 132 HCDR1 GFTFSSAA (IMGT) SEQ ID NO: 133 HCDR2 IKSKASGGTT(IMGT) SEQ ID NO: 134 HCDR3 ARDSPSISSYSIPYFSGMDV (IMGT) SEQ ID NO: 135VH QVQLVESGGGLVKPGGSLRLSCAASGFTFSSAAVHWVRQAPGKGLEWVGRIKSKASGGTTDYAAPVKGRFTISRDDSKNTLYLQMNSLKTEDTAVYYCARDSPSISSYSIPYFSGMDVWGQGTLVTVSS SEQ ID NO: 136 DNA VHCAAGTGCAGCTGGTGGAATCTGGCGGCGGACTGGTCAAGCCTGGCGGTAGCCTGAGACTGTCTTGCGCCGCCTCCGGCTTCACCTTCTCCTCTGCCGCTGTGCACTGGGTCCGACAGGCCCCTGGCAAGGGCCTGGAGTGGGTCGGACGGATCAAGTCCAAGGCCTCCGGCGGCACCACCGACTACGCTGCCCCTGTGAAGGGCCGGTTCACCATCTCCCGGGACGACTCCAAGAACACCCTGTACCTGCAGATGAACTCCCTGAAAACCGAGGACACCGCCGTGTACTACTGCGCCAGAGACTCCCCATCTATCTCCAGCTACTCCATCCCCTACTTCTCCGGCATGGACGTGTGGGGCCAGGGCACCCTGGTCACCGTGTCCTCT SEQ ID NO: 137 HeavyQVQLVESGGGLVKPGGSLRLSCAASGFTFSSAAVHWVRQAPGKG ChainLEWVGRIKSKASGGTTDYAAPVKGRFTISRDDSKNTLYLQMNSLKTEDTAVYYCARDSPSISSYSIPYFSGMDVWGQGTLVTVSSASTKGPSVFPLAPSSKSTSGGTAALGCLVKDYFPEPVTVSWNSGALTSGVHTFPAVLQSSGLYSLSSVVTVPSSSLGTQTYICNVNHKPSN TKVDKRVEPKSC SEQ ID NO: 138DNA CAAGTGCAGCTGGTGGAATCTGGCGGCGGACTGGTCAAGCCTGG HeavyCGGTAGCCTGAGACTGTCTTGCGCCGCCTCCGGCTTCACCTTCT ChainCCTCTGCCGCTGTGCACTGGGTCCGACAGGCCCCTGGCAAGGGCCTGGAGTGGGTCGGACGGATCAAGTCCAAGGCCTCCGGCGGCACCACCGACTACGCTGCCCCTGTGAAGGGCCGGTTCACCATCTCCCGGGACGACTCCAAGAACACCCTGTACCTGCAGATGAACTCCCTGAAAACCGAGGACACCGCCGTGTACTACTGCGCCAGAGACTCCCCATCTATCTCCAGCTACTCCATCCCCTACTTCTCCGGCATGGACGTGTGGGGCCAGGGCACCCTGGTCACCGTGTCCTCTGCTAGCACCAAGGGCCCCTCCGTGTTCCCTCTGGCCCCTTCCAGCAAGTCTACCTCTGGCGGCACCGCTGCTCTGGGCTGCCTGGTGAAGGACTACTTCCCTGAGCCTGTGACAGTGTCCTGGAACTCTGGCGCCCTGACCTCCGGCGTGCACACCTTCCCTGCCGTGCTGCAGTCCTCCGGCCTGTACTCCCTGTCCTCCGTGGTGACAGTGCCTTCCTCCAGCCTGGGCACCCAGACCTATATCTGCAACGTGAACCACAAGCCTTCCAACACCAAGGTGGACAAGCGGGTGGAGCCTAAGTCATGC SEQ ID NO: 139 LCDR1 RASQGIRAWLN(Combined) SEQ ID NO: 140 LCDR2 AASSLQS (Combined) SEQ ID NO: 141 LCDR3HQYITHPPT (Combined) SEQ ID NO: 142 LCDR1 RASQGIRAWLN (Kabat)SEQ ID NO: 143 LCDR2 AASSLQS (Kabat) SEQ ID NO: 144 LCDR3 HQYITHPPT(Kabat) SEQ ID NO: 145 LCDR1 SQGIRAW (Chothia) SEQ ID NO: 146 LCDR2 AAS(Chothia) SEQ ID NO: 147 LCDR3 YITHPP (Chothia) SEQ ID NO: 148 LCDR1QGIRAW (IMGT) SEQ ID NO: 149 LCDR2 AAS (IMGT) SEQ ID NO: 150 LCDR3HQYITHPPT (IMGT) SEQ ID NO: 151 VLDIQMTQSPSSLSASVGDRVTITCRASQGIRAWLNWYQQKPGKAPKLLIYAASSLQSGVPSRFSGSGSGTDFTLTISSLQPEDFATYYC HQYITHPPTFGQGTKVEIKSEQ ID NO: 152 DNA VL GACATCCAGATGACCCAGAGCCCCTCCAGCCTGTCCGCCTCCGTGGGCGACAGAGTGACCATCACCTGTCGGGCCTCTCAGGGCATCCGGGCCTGGCTGAACTGGTATCAGCAGAAGCCCGGCAAGGCCCCTAAGCTGCTGATCTACGCCGCCAGCTCCCTGCAGTCCGGCGTGCCCTCCAGATTCTCCGGCTCTGGCTCCGGCACCGACTTCACCCTGACCATCTCCAGCCTGCAGCCCGAGGACTTCGCCACCTACTACTGCCACCAGTACATCACCCACCCTCCCACCTTCGGCCAGGGCACCAA AGTGGAAATCAAGSEQ ID NO: 153 Light DIQMTQSPSSLSASVGDRVTITCRASQGIRAWLNWYQQKPGKAP ChainKLLIYAASSLQSGVPSRFSGSGSGTDFTLTISSLQPEDFATYYCHQYITHPPTFGQGTKVEIKRTVAAPSVFIFPPSDEQLKSGTASVVCLLNNFYPREAKVQWKVDNALQSGNSQESVTEQDSKDSTYSLSSTLTLSKADYEKHKVYACEVTHQGLSSPVTKSFNRGEC SEQ ID NO: 154 DNAGACATCCAGATGACCCAGAGCCCCTCCAGCCTGTCCGCCTCCGT LightGGGCGACAGAGTGACCATCACCTGTCGGGCCTCTCAGGGCATCC ChainGGGCCTGGCTGAACTGGTATCAGCAGAAGCCCGGCAAGGCCCCTAAGCTGCTGATCTACGCCGCCAGCTCCCTGCAGTCCGGCGTGCCCTCCAGATTCTCCGGCTCTGGCTCCGGCACCGACTTCACCCTGACCATCTCCAGCCTGCAGCCCGAGGACTTCGCCACCTACTACTGCCACCAGTACATCACCCACCCTCCCACCTTCGGCCAGGGCACCAAAGTGGAAATCAAGCGTACGGTGGCCGCTCCCAGCGTGTTCATCTTCCCCCCCAGCGACGAGCAGCTGAAGAGCGGCACCGCCAGCGTGGTGTGCCTGCTGAACAACTTCTACCCCCGGGAGGCCAAGGTGCAGTGGAAGGTGGACAACGCCCTGCAGAGCGGCAACAGCCAGGAGAGCGTCACCGAGCAGGACAGCAAGGACTCCACCTACAGCCTGAGCAGCACCCTGACCCTGAGCAAGGCCGACTACGAGAAGCATAAGGTGTACGCCTGCGAGGTGACCCACCAGGGCCTGTCCAGCCCCGTGA CCAAGAGCTTCAACAGGGGCGAGTGCIDT5 SEQ ID NO: 155 HCDR1 GFTFSSAAVH (Combined) SEQ ID NO: 156 HCDR2RIKSKADAGTTDYAAPVKG (Combined) SEQ ID NO: 157 HCDR3 DSPSISSYSIPYFSGMDV(Combined) SEQ ID NO: 158 HCDR1 SAAVH (Kabat) SEQ ID NO: 159 HCDR2RIKSKADAGTTDYAAPVKG (Kabat) SEQ ID NO: 160 HCDR3 DSPSISSYSIPYFSGMDV(Kabat) SEQ ID NO: 161 HCDR1 GFTFSSA (Chothia) SEQ ID NO: 162 HCDR2KSKADAGT (Chothia) SEQ ID NO: 163 HCDR3 DSPSISSYSIPYFSGMDV (Chothia)SEQ ID NO: 164 HCDR1 GFTFSSAA (IMGT) SEQ ID NO: 165 HCDR2 IKSKADAGTT(IMGT) SEQ ID NO: 166 HCDR3 ARDSPSISSYSIPYFSGMDV (IMGT) SEQ ID NO: 167VH QVQLVESGGGLVKPGGSLRLSCAASGFTFSSAAVHWVRQAPGKGLEWVGRIKSKADAGTIDYAAPVKGRFTISRDDSKNTLYLQMNSLKTEDTAVYYCARDSPSISSYSIPYFSGMDVWGQGTLVTVSS SEQ ID NO: 168 DNA VHCAAGTGCAGCTGGTGGAATCTGGCGGCGGACTGGTCAAGCCTGGCGGTAGCCTGAGACTGTCTTGCGCCGCCTCCGGCTTCACCTTCTCCTCTGCCGCTGTGCACTGGGTCCGACAGGCCCCTGGCAAGGGCCTGGAGTGGGTCGGACGGATCAAGTCCAAGGCCGACGCCGGCACCACCGACTACGCTGCCCCTGTGAAGGGCCGGTTCACCATCTCCCGGGACGACTCCAAGAACACCCTGTACCTGCAGATGAACTCCCTGAAAACCGAGGACACCGCCGTGTACTACTGCGCCAGAGACTCCCCATCTATCTCCAGCTACTCCATCCCCTACTTCTCCGGCATGGACGTGTGGGGCCAGGGCACCCTGGTCACCGTGTCCTCT SEQ ID NO: 169 HeavyQVQLVESGGGLVKPGGSLRLSCAASGFTFSSAAVHWVRQAPGKG ChainLEWVGRIKSKADAGTTDYAAPVKGRFTISRDDSKNTLYLQMNSLKTEDTAVYYCARDSPSISSYSIPYFSGMDVWGQGTLVTVSSASTKGPSVFPLAPSSKSTSGGTAALGCLVKDYFPEPVTVSWNSGALTSGVHTFPAVLQSSGLYSLSSVVTVPSSSLGTQTYICNVNHKPSN TKVDKRVEPKSC SEQ ID NO: 170DNA CAAGTGCAGCTGGTGGAATCTGGCGGCGGACTGGTCAAGCCTGG HeavyCGGTAGCCTGAGACTGTCTTGCGCCGCCTCCGGCTTCACCTTCT ChainCCTCTGCCGCTGTGCACTGGGTCCGACAGGCCCCTGGCAAGGGCCTGGAGTGGGTCGGACGGATCAAGTCCAAGGCCGACGCCGGCACCACCGACTACGCTGCCCCTGTGAAGGGCCGGTTCACCATCTCCCGGGACGACTCCAAGAACACCCTGTACCTGCAGATGAACTCCCTGAAAACCGAGGACACCGCCGTGTACTACTGCGCCAGAGACTCCCCATCTATCTCCAGCTACTCCATCCCCTACTTCTCCGGCATGGACGTGTGGGGCCAGGGCACCCTGGTCACCGTGTCCTCTGCTAGCACCAAGGGCCCCTCCGTGTTCCCTCTGGCCCCTTCCAGCAAGTCTACCTCTGGCGGCACCGCTGCTCTGGGCTGCCTGGTGAAGGACTACTTCCCTGAGCCTGTGACAGTGTCCTGGAACTCTGGCGCCCTGACCTCCGGCGTGCACACCTTCCCTGCCGTGCTGCAGTCCTCCGGCCTGTACTCCCTGTCCTCCGTGGTGACAGTGCCTTCCTCCAGCCTGGGCACCCAGACCTATATCTGCAACGTGAACCACAAGCCTTCCAACACCAAGGTGGACAAGCGGGTGGAGCCTAAGTCATGC SEQ ID NO: 171 LCDR1 RASQGIRAWLN(Combined) SEQ ID NO: 172 LCDR2 AASSLQS (Combined) SEQ ID NO: 173 LCDR3HQYITHPPT (Combined) SEQ ID NO: 174 LCDR1 RASQGIRAWLN (Kabat)SEQ ID NO: 175 LCDR2 AASSLQS (Kabat) SEQ ID NO: 176 LCDR3 HQYITHPPT(Kabat) SEQ ID NO: 177 LCDR1 SQGIRAW (Chothia) SEQ ID NO: 178 LCDR2 AAS(Chothia) SEQ ID NO: 179 LCDR3 YITHPP (Chothia) SEQ ID NO: 180 LCDR1QGIRAW (IMGT) SEQ ID NO: 181 LCDR2 AAS (IMGT) SEQ ID NO: 182 LCDR3HQYITHPPT (IMGT) SEQ ID NO: 183 VLDIQMTQSPSSLSASVGDRVTITCRASQGIRAWLNWYQQKPGKAPKLLIYAASSLQSGVPSRFSGSGSGTDFTLTISSLQPEDFATYYC HQYITHPPTFGQGTKVEIKSEQ ID NO: 184 DNA VL GACATCCAGATGACCCAGAGCCCCTCCAGCCTGTCCGCCTCCGTGGGCGACAGAGTGACCATCACCTGTCGGGCCTCTCAGGGCATCCGGGCCTGGCTGAACTGGTATCAGCAGAAGCCCGGCAAGGCCCCTAAGCTGCTGATCTACGCCGCCAGCTCCCTGCAGTCCGGCGTGCCCTCCAGATTCTCCGGCTCTGGCTCCGGCACCGACTTCACCCTGACCATCTCCAGCCTGCAGCCCGAGGACTTCGCCACCTACTACTGCCACCAGTACATCACCCACCCTCCCACCTTCGGCCAGGGCACCAA AGTGGAAATCAAGSEQ ID NO: 185 Light DIQMTQSPSSLSASVGDRVTITCRASQGIRAWLNWYQQKPGKAP ChainKLLIYAASSLQSGVPSRFSGSGSGTDFTLTISSLQPEDFATYYCHQYITHPPTFGQGTKVEIKRTVAAPSVFIFPPSDEQLKSGTASVVCLLNNFYPREAKVQWKVDNALQSGNSQESVTEQDSKDSTYSLSSTLTLSKADYEKHKVYACEVTHQGLSSPVTKSFNRGEC SEQ ID NO: 186 DNAGACATCCAGATGACCCAGAGCCCCTCCAGCCTGTCCGCCTCCGT LightGGGCGACAGAGTGACCATCACCTGTCGGGCCTCTCAGGGCATCC ChainGGGCCTGGCTGAACTGGTATCAGCAGAAGCCCGGCAAGGCCCCTAAGCTGCTGATCTACGCCGCCAGCTCCCTGCAGTCCGGCGTGCCCTCCAGATTCTCCGGCTCTGGCTCCGGCACCGACTTCACCCTGACCATCTCCAGCCTGCAGCCCGAGGACTTCGCCACCTACTACTGCCACCAGTACATCACCCACCCTCCCACCTTCGGCCAGGGCACCAAAGTGGAAATCAAGCGTACGGTGGCCGCTCCCAGCGTGTTCATCTTCCCCCCCAGCGACGAGCAGCTGAAGAGCGGCACCGCCAGCGTGGTGTGCCTGCTGAACAACTTCTACCCCCGGGAGGCCAAGGTGCAGTGGAAGGTGGACAACGCCCTGCAGAGCGGCAACAGCCAGGAGAGCGTCACCGAGCAGGACAGCAAGGACTCCACCTACAGCCTGAGCAGCACCCTGACCCTGAGCAAGGCCGACTACGAGAAGCATAAGGTGTACGCCTGCGAGGTGACCCACCAGGGCCTGTCCAGCCCCGTGA CCAAGAGCTTCAACAGGGGCGAGTGCIDT6 SEQ ID NO: 187 HCDR1 GYSFTNYWIG (Combined) SEQ ID NO: 188 HCDR2IIFPGVSYTKYSPSFQG (Combined) SEQ ID NO: 189 HCDR3 GSDQTLRGSRAMDY(Combined) SEQ ID NO: 190 HCDR1 NYWIG (Kabat) SEQ ID NO: 191 HCDR2IIFPGVSYTKYSPSFQG (Kabat) SEQ ID NO: 192 HCDR3 GSDQTLRGSRAMDY (Kabat)SEQ ID NO: 193 HCDR1 GYSFTNY (Chothia) SEQ ID NO: 194 HCDR2 FPGVSY(Chothia) SEQ ID NO: 195 HCDR3 GSDQTLRGSRAMDY (Chothia) SEQ ID NO: 196HCDR1 GYSFTNYW (IMGT) SEQ ID NO: 197 HCDR2 IFPGVSYT (IMGT)SEQ ID NO: 198 HCDR3 ARGSDQTLRGSRAMDY (IMGT) SEQ ID NO: 199 VHQVQLVQSGAEVKKPGESLKISCKGSGYSFTNYWIGWVRQMPGKGLEWMGIIFPGVSYTKYSPSFQGQVTISADKSISTAYLQWSSLKASDTAMYYCARGSDQTLRGSRAMDYWGQGTLVTVSS SEQ ID NO: 200 DNA VHCAAGTGCAGCTGGTGCAGTCTGGCGCTGAAGTGAAGAAGCCCGGCGAGTCCCTGAAGATCTCCTGCAAGGGCTCCGGCTACTCCTTCACCAACTACTGGATCGGCTGGGTCCGACAGATGCCCGGCAAGGGCCTGGAGTGGATGGGCATCATCTTCCCCGGCGTGTCCTACACCAAGTACAGCCCCAGCTTCCAGGGCCAAGTCACAATCTCCGCCGACAAGTCCATCTCCACCGCCTACCTGCAGTGGTCCTCCCTGAAGGCCTCCGACACCGCCATGTACTACTGCGCCAGAGGCTCCGACCAGACCCTGCGGGGCTCCAGAGCCATGGATTACTGGGGCCAGGGCACCC TGGTCACCGTGTCCTCTSEQ ID NO: 201 Heavy QVQLVQSGAEVKKPGESLKISCKGSGYSFTNYWIGWVRQMPGKG ChainLEWMGIIFPGVSYTKYSPSFQGQVTISADKSISTAYLQWSSLKASDTAMYYCARGSDQTLRGSRAMDYWGQGTLVTVSSASTKGPSVFPLAPSSKSTSGGTAALGCLVKDYFPEPVTVSWNSGALTSGVHTFPAVLQSSGLYSLSSVVTVPSSSLGTQTYICNVNHKPSNTKVDKR VEPKSC SEQ ID NO: 202 DNACAAGTGCAGCTGGTGCAGTCTGGCGCTGAAGTGAAGAAGCCCGG HeavyCGAGTCCCTGAAGATCTCCTGCAAGGGCTCCGGCTACTCCTTCA ChainCCAACTACTGGATCGGCTGGGTCCGACAGATGCCCGGCAAGGGCCTGGAGTGGATGGGCATCATCTTCCCCGGCGTGTCCTACACCAAGTACAGCCCCAGCTTCCAGGGCCAAGTCACAATCTCCGCCGACAAGTCCATCTCCACCGCCTACCTGCAGTGGTCCTCCCTGAAGGCCTCCGACACCGCCATGTACTACTGCGCCAGAGGCTCCGACCAGACCCTGCGGGGCTCCAGAGCCATGGATTACTGGGGCCAGGGCACCCTGGTCACCGTGTCCTCTGCTAGCACCAAGGGCCCCTCCGTGTTCCCTCTGGCCCCTTCCAGCAAGTCTACCTCTGGCGGCACCGCTGCTCTGGGCTGCCTGGTGAAGGACTACTTCCCTGAGCCTGTGACAGTGTCCTGGAACTCTGGCGCCCTGACCTCCGGCGTGCACACCTTCCCTGCCGTGCTGCAGTCCTCCGGCCTGTACTCCCTGTCCTCCGTGGTGACAGTGCCTTCCTCCAGCCTGGGCACCCAGACCTATATCTGCAACGTGAACCACAAGCCTTCCAACACCAAGGTGGACAAGCGG GTGGAGCCTAAGTCATGCSEQ ID NO: 203 LCDR1 TGTSSDVGISNYVS (Combined) SEQ ID NO: 204 LCDR2EVSNRPS (Combined) SEQ ID NO: 205 LCDR3 QSYTSLNYV (Combined)SEQ ID NO: 206 LCDR1 TGTSSDVGISNYVS (Kabat) SEQ ID NO: 207 LCDR2 EVSNRPS(Kabat) SEQ ID NO: 208 LCDR3 QSYTSLNYV (Kabat) SEQ ID NO: 209 LCDR1TSSDVGISNY (Chothia) SEQ ID NO: 210 LCDR2 EVS (Chothia) SEQ ID NO: 211LCDR3 YTSLNY (Chothia) SEQ ID NO: 212 LCDR1 SSDVGISNY (IMGT)SEQ ID NO: 213 LCDR2 EVS (IMGT) SEQ ID NO: 214 LCDR3 QSYTSLNYV (IMGT)SEQ ID NO: 215 VL QSALTQPASVSGSPGQSITISCTGTSSDVGISNYVSWYQQHPGKAPKLMIYEVSNRPSGVSNRFSGSKSGNTASLTISGLQAEDEADY YCQSYTSLNYVFGGGTKLTVLSEQ ID NO: 216 DNA VL CAGTCCGCCCTGACCCAGCCTGCCTCCGTGTCTGGCTCCCCTGGCCAGTCCATCACCATCAGCTGCACCGGCACCTCCAGCGACGTGGGCATCTCCAACTACGTGTCCTGGTATCAGCAGCACCCCGGCAAGGCCCCTAAGCTGATGATCTACGAAGTGTCCAACCGGCCCTCCGGCGTGTCCAACAGATTCTCCGGCTCCAAGTCCGGCAACACCGCCTCCCTGACCATCAGCGGCCTGCAGGCTGAGGACGAGGCCGACTACTACTGCCAGTCCTACACCTCCCTGAACTACGTGTTCGGCGGAGG CACCAAGCTGACCGTGCTGSEQ ID NO: 217 Light QSALTQPASVSGSPGQSITISCTGTSSDVGISNYVSWYQQHPGK ChainAPKLMIYEVSNRPSGVSNRFSGSKSGNTASLTISGLQAEDEADYYCQSYTSLNYVFGGGTKLTVLGQPKAAPSVTLFPPSSEELQANKATLVCLISDFYPGAVTVAWKADSSPVKAGVETTTPSKQSNNKYAASSYLSLTPEQWKSHRSYSCQVTHEGSTVEKTVAPTECS SEQ ID NO: 218 DNACAGTCCGCCCTGACCCAGCCTGCCTCCGTGTCTGGCTCCCCTGG LightCCAGTCCATCACCATCAGCTGCACCGGCACCTCCAGCGACGTGG ChainGCATCTCCAACTACGTGTCCTGGTATCAGCAGCACCCCGGCAAGGCCCCTAAGCTGATGATCTACGAAGTGTCCAACCGGCCCTCCGGCGTGTCCAACAGATTCTCCGGCTCCAAGTCCGGCAACACCGCCTCCCTGACCATCAGCGGCCTGCAGGCTGAGGACGAGGCCGACTACTACTGCCAGTCCTACACCTCCCTGAACTACGTGTTCGGCGGAGGCACCAAGCTGACCGTGCTGGGCCAGCCTAAGGCTGCCCCCAGCGTGACCCTGTTCCCCCCCAGCAGCGAGGAGCTGCAGGCCAACAAGGCCACCCTGGTGTGCCTGATCAGCGACTTCTACCCAGGCGCCGTGACCGTGGCCTGGAAGGCCGACAGCAGCCCCGTGAAGGCCGGCGTGGAGACCACCACCCCCAGCAAGCAGAGCAACAACAAGTACGCCGCCAGCAGCTACCTGAGCCTGACCCCCGAGCAGTGGAAGAGCCACAGGTCCTACAGCTGCCAGGTGACCCACGAGGGCAGCACCGTGGAAAAGACCGTGGCCCCAACCGAGTGCAGC IDT7 SEQ ID NO: 219 HCDR1 GFTFSSNAMH(Combined) SEQ ID NO: 220 HCDR2 RIKSKTDGGTTDYAAPVKG (Combined)SEQ ID NO: 221 HCDR3 DHYYYPFAY (Combined) SEQ ID NO: 222 HCDR1 SNAMH(Kabat) SEQ ID NO: 223 HCDR2 RIKSKTDGGTTDYAAPVKG (Kabat) SEQ ID NO: 224HCDR3 DHYYYPFAY (Kabat) SEQ ID NO: 225 HCDR1 GFTFSSN (Chothia)SEQ ID NO: 226 HCDR2 KSKTDGGT (Chothia) SEQ ID NO: 227 HCDR3 DHYYYPFAY(Chothia) SEQ ID NO: 228 HCDR1 GFTFSSNA (IMGT) SEQ ID NO: 229 HCDR2IKSKTDGGTT (IMGT) SEQ ID NO: 230 HCDR3 ARDHYYYPFAY (IMGT) SEQ ID NO: 231VH QVQLVESGGGLVKPGGSLRLSCAASGFTFSSNAMHWVRQAPGKGLEWVGRIKSKTDGGTTDYAAPVKGRFTISRDDSKNTLYLQMNSLKTEDTAVYYCARDHYYYPFAYWGQGTLVTVSS SEQ ID NO: 232 DNA VHCAAGTGCAGCTGGTGGAATCTGGCGGCGGACTGGTCAAGCCTGGCGGTAGCCTGAGACTGTCTTGCGCCGCCTCCGGCTTCACCTTCTCCTCCAACGCCATGCACTGGGTCCGACAGGCCCCTGGCAAGGGCCTGGAGTGGGTCGGACGGATCAAGTCCAAGACCGACGGCGGCACCACCGACTACGCTGCCCCTGTGAAGGGCCGGTTCACCATCTCCCGGGACGACTCCAAGAACACCCTGTACCTGCAGATGAACTCCCTGAAAACCGAGGACACCGCCGTGTACTACTGCGCCAGGGACCACTACTACTACCCCTTCGCCTACTGGGGCCAGGGCACCCTGGTCACCG TGTCCTCT SEQ ID NO: 233Heavy QVQLVESGGGLVKPGGSLRLSCAASGFTFSSNAMHWVRQAPGKG ChainLEWVGRIKSKTDGGTTDYAAPVKGRFTISRDDSKNTLYLQMNSLKTEDTAVYYCARDHYYYPFAYWGQGTLVTVSSASTKGPSVFPLAPSSKSTSGGTAALGCLVKDYFPEPVTVSWNSGALTSGVHTFPAVLQSSGLYSLSSVVTVPSSSLGTQTYICNVNHKPSNTKVDKRVEP KSC SEQ ID NO: 234 DNACAAGTGCAGCTGGTGGAATCTGGCGGCGGACTGGTCAAGCCTGG HeavyCGGTAGCCTGAGACTGTCTTGCGCCGCCTCCGGCTTCACCTTCT ChainCCTCCAACGCCATGCACTGGGTCCGACAGGCCCCTGGCAAGGGCCTGGAGTGGGTCGGACGGATCAAGTCCAAGACCGACGGCGGCACCACCGACTACGCTGCCCCTGTGAAGGGCCGGTTCACCATCTCCCGGGACGACTCCAAGAACACCCTGTACCTGCAGATGAACTCCCTGAAAACCGAGGACACCGCCGTGTACTACTGCGCCAGGGACCACTACTACTACCCCTTCGCCTACTGGGGCCAGGGCACCCTGGTCACCGTGTCCTCTGCTAGCACCAAGGGCCCCTCCGTGTTCCCTCTGGCCCCTTCCAGCAAGTCTACCTCTGGCGGCACCGCTGCTCTGGGCTGCCTGGTGAAGGACTACTTCCCTGAGCCTGTGACAGTGTCCTGGAACTCTGGCGCCCTGACCTCCGGCGTGCACACCTTCCCTGCCGTGCTGCAGTCCTCCGGCCTGTACTCCCTGTCCTCCGTGGTGACAGTGCCTTCCTCCAGCCTGGGCACCCAGACCTATATCTGCAACGTGAACCACAAGCCTTCCAACACCAAGGTGGACAAGCGGGTGGAGCCT AAGTCATGC SEQ ID NO: 235LCDR1 RASQSIRYNLA (Combined) SEQ ID NO: 236 LCDR2 AASSLQS (Combined)SEQ ID NO: 237 LCDR3 HQYIAKPIT (Combined) SEQ ID NO: 238 LCDR1RASQSIRYNLA (Kabat) SEQ ID NO: 239 LCDR2 AASSLQS (Kabat) SEQ ID NO: 240LCDR3 HQYIAKPIT (Kabat) SEQ ID NO: 241 LCDR1 SQSIRYN (Chothia)SEQ ID NO: 242 LCDR2 AAS (Chothia) SEQ ID NO: 243 LCDR3 YIAKPI (Chothia)SEQ ID NO: 244 LCDR1 QSIRYN (IMGT) SEQ ID NO: 245 LCDR2 AAS (IMGT)SEQ ID NO: 246 LCDR3 HQYIAKPIT (IMGT) SEQ ID NO: 247 VLDIQMTQSPSSLSASVGDRVTITCRASQSIRYNLAWYQQKPGKAPKLLIYAASSLQSGVPSRFSGSGSGTDFTLTISSLQPEDFATYYC HQYIAKPITFGQGTKVEIKSEQ ID NO: 248 DNA VL GACATCCAGATGACCCAGAGCCCCTCCAGCCTGTCCGCCTCCGTGGGCGACAGAGTGACCATCACCTGTCGGGCCTCCCAGTCCATCCGGTACAACCTGGCCTGGTATCAGCAGAAGCCCGGCAAGGCCCCTAAGCTGCTGATCTACGCCGCCAGCTCCCTGCAGTCCGGCGTGCCCTCCAGATTCTCCGGCTCTGGCTCCGGCACCGACTTCACCCTGACCATCTCCAGCCTGCAGCCCGAGGACTTCGCCACCTACTACTGCCACCAGTATATCGCCAAGCCCATCACCTTCGGCCAGGGCACCAA AGTGGAAATCAAGSEQ ID NO: 249 Light DIQMTQSPSSLSASVGDRVTITCRASQSIRYNLAWYQQKPGKAP ChainKLLIYAASSLQSGVPSRFSGSGSGTDFTLTISSLQPEDFATYYCHQYIAKPITFGQGTKVEIKRTVAAPSVFIFPPSDEQLKSGTASVVCLLNNFYPREAKVQWKVDNALQSGNSQESVTEQDSKDSTYSLSSTLTLSKADYEKHKVYACEVTHQGLSSPVTKSFNRGEC SEQ ID NO: 250 DNAGACATCCAGATGACCCAGAGCCCCTCCAGCCTGTCCGCCTCCGT LightGGGCGACAGAGTGACCATCACCTGTCGGGCCTCCCAGTCCATCC ChainGGTACAACCTGGCCTGGTATCAGCAGAAGCCCGGCAAGGCCCCTAAGCTGCTGATCTACGCCGCCAGCTCCCTGCAGTCCGGCGTGCCCTCCAGATTCTCCGGCTCTGGCTCCGGCACCGACTTCACCCTGACCATCTCCAGCCTGCAGCCCGAGGACTTCGCCACCTACTACTGCCACCAGTATATCGCCAAGCCCATCACCTTCGGCCAGGGCACCAAAGTGGAAATCAAGCGTACGGTGGCCGCTCCCAGCGTGTTCATCTTCCCCCCCAGCGACGAGCAGCTGAAGAGCGGCACCGCCAGCGTGGTGTGCCTGCTGAACAACTTCTACCCCCGGGAGGCCAAGGTGCAGTGGAAGGTGGACAACGCCCTGCAGAGCGGCAACAGCCAGGAGAGCGTCACCGAGCAGGACAGCAAGGACTCCACCTACAGCCTGAGCAGCACCCTGACCCTGAGCAAGGCCGACTACGAGAAGCATAAGGTGTACGCCTGCGAGGTGACCCACCAGGGCCTGTCCAGCCCCGTGA CCAAGAGCTTCAACAGGGGCGAGTGCIDT8 SEQ ID NO: 251 HCDR1 GFTFSSNAMH (Combined) SEQ ID NO: 252 HCDR2RIKSKTSGGTTDYAAPVKG (Combined) SEQ ID NO: 253 HCDR3 DHYYYPFAY (Combined)SEQ ID NO: 254 HCDR1 SNAMH (Kabat) SEQ ID NO: 255 HCDR2RIKSKTSGGTTDYAAPVKG (Kabat) SEQ ID NO: 256 HCDR3 DHYYYPFAY (Kabat)SEQ ID NO: 257 HCDR1 GFTFSSN (Chothia) SEQ ID NO: 258 HCDR2 KSKTSGGT(Chothia) SEQ ID NO: 259 HCDR3 DHYYYPFAY (Chothia) SEQ ID NO: 260 HCDR1GFTFSSNA (IMGT) SEQ ID NO: 261 HCDR2 IKSKTSGGTT (IMGT) SEQ ID NO: 262HCDR3 ARDHYYYPFAY (IMGT) SEQ ID NO: 263 VHQVQLVESGGGLVKPGGSLRLSCAASGFTFSSNAMHWVRQAPGKGLEWVGRIKSKTSGGTTDYAAPVKGRFTISRDDSKNTLYLQMNSLKTEDTAVYYCARDHYYYPFAYWGQGTLVTVSS SEQ ID NO: 264 DNA VHCAAGTGCAGCTGGTGGAATCTGGCGGCGGACTGGTCAAGCCTGGCGGTAGCCTGAGACTGTCTTGCGCCGCCTCCGGCTTCACCTTCTCCTCCAACGCCATGCACTGGGTCCGACAGGCCCCTGGCAAGGGCCTGGAGTGGGTCGGACGGATCAAGTCCAAGACCTCCGGCGGCACCACCGACTACGCTGCCCCTGTGAAGGGCCGGTTCACCATCTCCCGGGACGACTCCAAGAACACCCTGTACCTGCAGATGAACTCCCTGAAAACCGAGGACACCGCCGTGTACTACTGCGCCAGGGACCACTACTACTACCCCTTCGCCTACTGGGGCCAGGGCACCCTGGTCACCG TGTCCTCT SEQ ID NO: 265Heavy QVQLVESGGGLVKPGGSLRLSCAASGFTFSSNAMHWVRQAPGKG ChainLEWVGRIKSKTSGGTTDYAAPVKGRFTISRDDSKNTLYLQMNSLKTEDTAVYYCARDHYYYPFAYWGQGTLVTVSSASTKGPSVFPLAPSSKSTSGGTAALGCLVKDYFPEPVTVSWNSGALTSGVHTFPAVLQSSGLYSLSSVVTVPSSSLGTQTYICNVNHKPSNTKVDKRVEP KSC SEQ ID NO: 266 DNACAAGTGCAGCTGGTGGAATCTGGCGGCGGACTGGTCAAGCCTGG HeavyCGGTAGCCTGAGACTGTCTTGCGCCGCCTCCGGCTTCACCTTCT ChainCCTCCAACGCCATGCACTGGGTCCGACAGGCCCCTGGCAAGGGCCTGGAGTGGGTCGGACGGATCAAGTCCAAGACCTCCGGCGGCACCACCGACTACGCTGCCCCTGTGAAGGGCCGGTTCACCATCTCCCGGGACGACTCCAAGAACACCCTGTACCTGCAGATGAACTCCCTGAAAACCGAGGACACCGCCGTGTACTACTGCGCCAGGGACCACTACTACTACCCCTTCGCCTACTGGGGCCAGGGCACCCTGGTCACCGTGTCCTCTGCTAGCACCAAGGGCCCCTCCGTGTTCCCTCTGGCCCCTTCCAGCAAGTCTACCTCTGGCGGCACCGCTGCTCTGGGCTGCCTGGTGAAGGACTACTTCCCTGAGCCTGTGACAGTGTCCTGGAACTCTGGCGCCCTGACCTCCGGCGTGCACACCTTCCCTGCCGTGCTGCAGTCCTCCGGCCTGTACTCCCTGTCCTCCGTGGTGACAGTGCCTTCCTCCAGCCTGGGCACCCAGACCTATATCTGCAACGTGAACCACAAGCCTTCCAACACCAAGGTGGACAAGCGGGTGGAGCCT AAGTCATGC SEQ ID NO: 267LCDR1 RASQSIRYNLA (Combined) SEQ ID NO: 268 LCDR2 AASSLQS (Combined)SEQ ID NO: 269 LCDR3 HQYIAKPIT (Combined) SEQ ID NO: 270 LCDR1RASQSIRYNLA (Kabat) SEQ ID NO: 271 LCDR2 AASSLQS (Kabat) SEQ ID NO: 272LCDR3 HQYIAKPIT (Kabat) SEQ ID NO: 273 LCDR1 SQSIRYN (Chothia)SEQ ID NO: 274 LCDR2 AAS (Chothia) SEQ ID NO: 275 LCDR3 YIAKPI (Chothia)SEQ ID NO: 276 LCDR1 QSIRYN (IMGT) SEQ ID NO: 277 LCDR2 AAS (IMGT)SEQ ID NO: 278 LCDR3 HQYIAKPIT (IMGT) SEQ ID NO: 279 VLDIQMTQSPSSLSASVGDRVTITCRASQSIRYNLAWYQQKPGKAPKLLIYAASSLQSGVPSRFSGSGSGTDFTLTISSLQPEDFATYYC HQYIAKPITFGQGTKVEIKSEQ ID NO: 280 DNA VL GACATCCAGATGACCCAGAGCCCCTCCAGCCTGTCCGCCTCCGTGGGCGACAGAGTGACCATCACCTGTCGGGCCTCCCAGTCCATCCGGTACAACCTGGCCTGGTATCAGCAGAAGCCCGGCAAGGCCCCTAAGCTGCTGATCTACGCCGCCAGCTCCCTGCAGTCCGGCGTGCCCTCCAGATTCTCCGGCTCTGGCTCCGGCACCGACTTCACCCTGACCATCTCCAGCCTGCAGCCCGAGGACTTCGCCACCTACTACTGCCACCAGTATATCGCCAAGCCCATCACCTTCGGCCAGGGCACCAA AGTGGAAATCAAGSEQ ID NO: 281 Light DIQMTQSPSSLSASVGDRVTITCRASQSIRYNLAWYQQKPGKAP ChainKLLIYAASSLQSGVPSRFSGSGSGTDFTLTISSLQPEDFATYYCHQYIAKPITFGQGTKVEIKRTVAAPSVFIFPPSDEQLKSGTASVVCLLNNFYPREAKVQWKVDNALQSGNSQESVTEQDSKDSTYSLSSTLTLSKADYEKHKVYACEVTHQGLSSPVTKSFNRGEC SEQ ID NO: 282 DNAGACATCCAGATGACCCAGAGCCCCTCCAGCCTGTCCGCCTCCGT LightGGGCGACAGAGTGACCATCACCTGTCGGGCCTCCCAGTCCATCC ChainGGTACAACCTGGCCTGGTATCAGCAGAAGCCCGGCAAGGCCCCTAAGCTGCTGATCTACGCCGCCAGCTCCCTGCAGTCCGGCGTGCCCTCCAGATTCTCCGGCTCTGGCTCCGGCACCGACTTCACCCTGACCATCTCCAGCCTGCAGCCCGAGGACTTCGCCACCTACTACTGCCACCAGTATATCGCCAAGCCCATCACCTTCGGCCAGGGCACCAAAGTGGAAATCAAGCGTACGGTGGCCGCTCCCAGCGTGTTCATCTTCCCCCCCAGCGACGAGCAGCTGAAGAGCGGCACCGCCAGCGTGGTGTGCCTGCTGAACAACTTCTACCCCCGGGAGGCCAAGGTGCAGTGGAAGGTGGACAACGCCCTGCAGAGCGGCAACAGCCAGGAGAGCGTCACCGAGCAGGACAGCAAGGACTCCACCTACAGCCTGAGCAGCACCCTGACCCTGAGCAAGGCCGACTACGAGAAGCATAAGGTGTACGCCTGCGAGGTGACCCACCAGGGCCTGTCCAGCCCCGTGA CCAAGAGCTTCAACAGGGGCGAGTGCIDT9 SEQ ID NO: 283 HCDR1 GYTFTNYYVH (Combined) SEQ ID NO: 284 HCDR2WINPYNGNTNYAQKFQG (Combined) SEQ ID NO: 285 HCDR3 GASSIRMSYYLDV(Combined) SEQ ID NO: 286 HCDR1 NYYVH (Kabat) SEQ ID NO: 287 HCDR2WINPYNGNTNYAQKFQG (Kabat) SEQ ID NO: 288 HCDR3 GASSIRMSYYLDV (Kabat)SEQ ID NO: 289 HCDR1 GYTFTNY (Chothia) SEQ ID NO: 290 HCDR2 NPYNGN(Chothia) SEQ ID NO: 291 HCDR3 GASSIRMSYYLDV (Chothia) SEQ ID NO: 292HCDR1 GYTFTNYY (IMGT) SEQ ID NO: 293 HCDR2 INPYNGNT (IMGT)SEQ ID NO: 294 HCDR3 ARGASSIRMSYYLDV (IMGT) SEQ ID NO: 295 VHQVQLVQSGAEVKKPGASVKVSCKASGYTFTNYYVHWVRQAPGQGLEWMGWINPYNGNTNYAQKFQGRVTMTRDTSISTAYMELSRLRSEDTAVYYCARGASSIRMSYYLDVWGQGTLVTVSS SEQ ID NO: 296 DNA VHCAAGTGCAGCTGGTGCAGTCTGGCGCTGAAGTGAAGAAACCTGGCGCCTCCGTGAAAGTGTCCTGCAAGGCCTCCGGCTACACCTTCACCAACTACTACGTGCACTGGGTCCGACAGGCCCCAGGCCAGGGCCTGGAGTGGATGGGCTGGATCAACCCCTACAACGGCAACACCAACTACGCCCAGAAATTCCAGGGCAGAGTGACCATGACCCGGGACACCTCCATCTCCACCGCCTACATGGAACTGTCCCGGCTGCGGAGCGAGGACACCGCCGTGTACTACTGTGCCAGAGGCGCCTCCTCCATCCGGATGTCCTACTACCTGGACGTGTGGGGCCAGGGCACCCTGG TCACCGTGTCCTCTSEQ ID NO: 297 Heavy QVQLVQSGAEVKKPGASVKVSCKASGYTFTNYYVHWVRQAPGQG ChainLEWMGWINPYNGNTNYAQKFQGRVTMTRDTSISTAYMELSRLRSEDTAVYYCARGASSIRMSYYLDVWGQGTLVTVSSASTKGPSVFPLAPSSKSTSGGTAALGCLVKDYFPEPVTVSWNSGALTSGVHTFPAVLQSSGLYSLSSVVTVPSSSLGTQTYICNVNHKPSNTKVDKRV EPKSC SEQ ID NO: 298 DNACAAGTGCAGCTGGTGCAGTCTGGCGCTGAAGTGAAGAAACCTGG HeavyCGCCTCCGTGAAAGTGTCCTGCAAGGCCTCCGGCTACACCTTCA ChainCCAACTACTACGTGCACTGGGTCCGACAGGCCCCAGGCCAGGGCCTGGAGTGGATGGGCTGGATCAACCCCTACAACGGCAACACCAACTACGCCCAGAAATTCCAGGGCAGAGTGACCATGACCCGGGACACCTCCATCTCCACCGCCTACATGGAACTGTCCCGGCTGCGGAGCGAGGACACCGCCGTGTACTACTGTGCCAGAGGCGCCTCCTCCATCCGGATGTCCTACTACCTGGACGTGTGGGGCCAGGGCACCCTGGTCACCGTGTCCTCTGCTAGCACCAAGGGCCCCTCCGTGTTCCCTCTGGCCCCTTCCAGCAAGTCTACCTCTGGCGGCACCGCTGCTCTGGGCTGCCTGGTGAAGGACTACTTCCCTGAGCCTGTGACAGTGTCCTGGAACTCTGGCGCCCTGACCTCCGGCGTGCACACCTTCCCTGCCGTGCTGCAGTCCTCCGGCCTGTACTCCCTGTCCTCCGTGGTGACAGTGCCTTCCTCCAGCCTGGGCACCCAGACCTATATCTGCAACGTGAACCACAAGCCTTCCAACACCAAGGTGGACAAGCGGGTG GAGCCTAAGTCATGCSEQ ID NO: 299 LCDR1 RASQSISNYLN (Combined) SEQ ID NO: 300 LCDR2 AASNLQS(Combined) SEQ ID NO: 301 LCDR3 FQYTHSPAT (Combined) SEQ ID NO: 302LCDR1 RASQSISNYLN (Kabat) SEQ ID NO: 303 LCDR2 AASNLQS (Kabat)SEQ ID NO: 304 LCDR3 FQYTHSPAT (Kabat) SEQ ID NO: 305 LCDR1 SQSISNY(Chothia) SEQ ID NO: 306 LCDR2 AAS (Chothia) SEQ ID NO: 307 LCDR3 YTHSPA(Chothia) SEQ ID NO: 308 LCDR1 QSISNY (IMGT) SEQ ID NO: 309 LCDR2 AAS(IMGT) SEQ ID NO: 310 LCDR3 FQYTHSPAT (IMGT) SEQ ID NO: 311 VLDIQMTQSPSSLSASVGDRVTITCRASQSISNYLNWYQQKPGKAPKLLIYAASNLQSGVPSRFSGSGSGTDFTLTISSLQPEDFATYYC FQYTHSPATFGQGTKVEIKSEQ ID NO: 312 DNA VL GACATCCAGATGACCCAGAGCCCCTCCAGCCTGTCCGCCTCCGTGGGCGACAGAGTGACCATCACCTGTCGGGCCTCCCAGTCCATCTCCAACTACCTGAACTGGTATCAGCAGAAGCCCGGCAAGGCCCCTAAGCTGCTGATCTACGCCGCCTCCAACCTGCAGTCCGGCGTGCCCTCCAGATTCTCCGGCTCTGGCTCCGGCACCGACTTCACCCTGACCATCTCCAGCCTGCAGCCCGAGGACTTCGCCACCTACTACTGCTTCCAGTACACCCACAGCCCCGCCACCTTCGGCCAGGGCACCAA AGTGGAAATCAAGSEQ ID NO: 313 Light DIQMTQSPSSLSASVGDRVTITCRASQSISNYLNWYQQKPGKAP ChainKLLIYAASNLQSGVPSRFSGSGSGTDFTLTISSLQPEDFATYYCFQYTHSPATFGQGTKVEIKRTVAAPSVFIFPPSDEQLKSGTASVVCLLNNFYPREAKVQWKVDNALQSGNSQESVTEQDSKDSTYSLSSTLTLSKADYEKHKVYACEVTHQGLSSPVTKSFNRGEC SEQ ID NO: 314 DNAGACATCCAGATGACCCAGAGCCCCTCCAGCCTGTCCGCCTCCGT LightGGGCGACAGAGTGACCATCACCTGTCGGGCCTCCCAGTCCATCT ChainCCAACTACCTGAACTGGTATCAGCAGAAGCCCGGCAAGGCCCCTAAGCTGCTGATCTACGCCGCCTCCAACCTGCAGTCCGGCGTGCCCTCCAGATTCTCCGGCTCTGGCTCCGGCACCGACTTCACCCTGACCATCTCCAGCCTGCAGCCCGAGGACTTCGCCACCTACTACTGCTTCCAGTACACCCACAGCCCCGCCACCTTCGGCCAGGGCACCAAAGTGGAAATCAAGCGTACGGTGGCCGCTCCCAGCGTGTTCATCTTCCCCCCCAGCGACGAGCAGCTGAAGAGCGGCACCGCCAGCGTGGTGTGCCTGCTGAACAACTTCTACCCCCGGGAGGCCAAGGTGCAGTGGAAGGTGGACAACGCCCTGCAGAGCGGCAACAGCCAGGAGAGCGTCACCGAGCAGGACAGCAAGGACTCCACCTACAGCCTGAGCAGCACCCTGACCCTGAGCAAGGCCGACTACGAGAAGCATAAGGTGTACGCCTGCGAGGTGACCCACCAGGGCCTGTCCAGCCCCGTGA CCAAGAGCTTCAACAGGGGCGAGTGCIDT10 SEQ ID NO: 315 HCDR1 GYTFTNYYVH (Combined) SEQ ID NO: 316 HCDR2WINPYSGNTNYAQKFQG (Combined) SEQ ID NO: 317 HCDR3 GASSIRMSYYLDV(Combined) SEQ ID NO: 318 HCDR1 NYYVH (Kabat) SEQ ID NO: 319 HCDR2WINPYSGNTNYAQKFQG (Kabat) SEQ ID NO: 320 HCDR3 GASSIRMSYYLDV (Kabat)SEQ ID NO: 321 HCDR1 GYTFTNY (Chothia) SEQ ID NO: 322 HCDR2 NPYSGN(Chothia) SEQ ID NO: 323 HCDR3 GASSIRMSYYLDV (Chothia) SEQ ID NO: 324HCDR1 GYTFTNYY (IMGT) SEQ ID NO: 325 HCDR2 INPYSGNT (IMGT)SEQ ID NO: 326 HCDR3 ARGASSIRMSYYLDV (IMGT) SEQ ID NO: 327 VHQVQLVQSGAEVKKPGASVKVSCKASGYTFTNYYVHWVRQAPGQGLEWMGWINPYSGNTNYAQKFQGRVTMTRDTSISTAYMELSRLRSEDTAVYYCARGASSIRMSYYLDVWGQGTLVTVSS SEQ ID NO: 328 DNA VHCAAGTGCAGCTGGTGCAGTCTGGCGCTGAAGTGAAGAAACCTGGCGCCTCCGTGAAAGTGTCCTGCAAGGCCTCCGGCTACACCTTCACCAACTACTACGTGCACTGGGTCCGACAGGCCCCAGGCCAGGGCCTGGAGTGGATGGGCTGGATCAACCCCTACTCCGGCAACACCAACTACGCCCAGAAATTCCAGGGCAGAGTGACCATGACCCGGGACACCTCCATCTCCACCGCCTACATGGAACTGTCCCGGCTGCGGAGCGAGGACACCGCCGTGTACTACTGTGCCAGAGGCGCCTCCTCCATCCGGATGTCCTACTACCTGGACGTGTGGGGCCAGGGCACCCTGG TCACCGTGTCCTCTSEQ ID NO: 329 Heavy QVQLVQSGAEVKKPGASVKVSCKASGYTFTNYYVHWVRQAPGQG ChainLEWMGWINPYSGNTNYAQKFQGRVTMTRDTSISTAYMELSRLRSEDTAVYYCARGASSIRMSYYLDVWGQGTLVTVSSASTKGPSVFPLAPSSKSTSGGTAALGCLVKDYFPEPVTVSWNSGALTSGVHTFPAVLQSSGLYSLSSVVTVPSSSLGTQTYICNVNHKPSNTKVDKRV EPKSC SEQ ID NO: 330 DNACAAGTGCAGCTGGTGCAGTCTGGCGCTGAAGTGAAGAAACCTGG HeavyCGCCTCCGTGAAAGTGTCCTGCAAGGCCTCCGGCTACACCTTCA ChainCCAACTACTACGTGCACTGGGTCCGACAGGCCCCAGGCCAGGGCCTGGAGTGGATGGGCTGGATCAACCCCTACTCCGGCAACACCAACTACGCCCAGAAATTCCAGGGCAGAGTGACCATGACCCGGGACACCTCCATCTCCACCGCCTACATGGAACTGTCCCGGCTGCGGAGCGAGGACACCGCCGTGTACTACTGTGCCAGAGGCGCCTCCTCCATCCGGATGTCCTACTACCTGGACGTGTGGGGCCAGGGCACCCTGGTCACCGTGTCCTCTGCTAGCACCAAGGGCCCCTCCGTGTTCCCTCTGGCCCCTTCCAGCAAGTCTACCTCTGGCGGCACCGCTGCTCTGGGCTGCCTGGTGAAGGACTACTTCCCTGAGCCTGTGACAGTGTCCTGGAACTCTGGCGCCCTGACCTCCGGCGTGCACACCTTCCCTGCCGTGCTGCAGTCCTCCGGCCTGTACTCCCTGTCCTCCGTGGTGACAGTGCCTTCCTCCAGCCTGGGCACCCAGACCTATATCTGCAACGTGAACCACAAGCCTTCCAACACCAAGGTGGACAAGCGGGTG GAGCCTAAGTCATGCSEQ ID NO: 331 LCDR1 RASQSISNYLN (Combined) SEQ ID NO: 332 LCDR2 AASNLQS(Combined) SEQ ID NO: 333 LCDR3 FQYTHSPAT (Combined) SEQ ID NO: 334LCDR1 RASQSISNYLN (Kabat) SEQ ID NO: 335 LCDR2 AASNLQS (Kabat)SEQ ID NO: 336 LCDR3 FQYTHSPAT (Kabat) SEQ ID NO: 337 LCDR1 SQSISNY(Chothia) SEQ ID NO: 338 LCDR2 AAS (Chothia) SEQ ID NO: 339 LCDR3 YTHSPA(Chothia) SEQ ID NO: 340 LCDR1 QSISNY (IMGT) SEQ ID NO: 341 LCDR2 AAS(IMGT) SEQ ID NO: 342 LCDR3 FQYTHSPAT (IMGT) SEQ ID NO: 343 VLDIQMTQSPSSLSASVGDRVTITCRASQSISNYLNWYQQKPGKAPKLLIYAASNLQSGVPSRFSGSGSGTDFTLTISSLQPEDFATYYC FQYTHSPATFGQGTKVEIKSEQ ID NO: 344 DNA VL GACATCCAGATGACCCAGAGCCCCTCCAGCCTGTCCGCCTCCGTGGGCGACAGAGTGACCATCACCTGTCGGGCCTCCCAGTCCATCTCCAACTACCTGAACTGGTATCAGCAGAAGCCCGGCAAGGCCCCTAAGCTGCTGATCTACGCCGCCTCCAACCTGCAGTCCGGCGTGCCCTCCAGATTCTCCGGCTCTGGCTCCGGCACCGACTTCACCCTGACCATCTCCAGCCTGCAGCCCGAGGACTTCGCCACCTACTACTGCTTCCAGTACACCCACAGCCCCGCCACCTTCGGCCAGGGCACCAA AGTGGAAATCAAGSEQ ID NO: 345 Light DIQMTQSPSSLSASVGDRVTITCRASQSISNYLNWYQQKPGKAP ChainKLLIYAASNLQSGVPSRFSGSGSGTDFTLTISSLQPEDFATYYCFQYTHSPATFGQGTKVEIKRTVAAPSVFIFPPSDEQLKSGTASVVCLLNNFYPREAKVQWKVDNALQSGNSQESVTEQDSKDSTYSLSSTLTLSKADYEKHKVYACEVTHQGLSSPVTKSFNRGEC SEQ ID NO: 346 DNAGACATCCAGATGACCCAGAGCCCCTCCAGCCTGTCCGCCTCCGT LightGGGCGACAGAGTGACCATCACCTGTCGGGCCTCCCAGTCCATCT ChainCCAACTACCTGAACTGGTATCAGCAGAAGCCCGGCAAGGCCCCTAAGCTGCTGATCTACGCCGCCTCCAACCTGCAGTCCGGCGTGCCCTCCAGATTCTCCGGCTCTGGCTCCGGCACCGACTTCACCCTGACCATCTCCAGCCTGCAGCCCGAGGACTTCGCCACCTACTACTGCTTCCAGTACACCCACAGCCCCGCCACCTTCGGCCAGGGCACCAAAGTGGAAATCAAGCGTACGGTGGCCGCTCCCAGCGTGTTCATCTTCCCCCCCAGCGACGAGCAGCTGAAGAGCGGCACCGCCAGCGTGGTGTGCCTGCTGAACAACTTCTACCCCCGGGAGGCCAAGGTGCAGTGGAAGGTGGACAACGCCCTGCAGAGCGGCAACAGCCAGGAGAGCGTCACCGAGCAGGACAGCAAGGACTCCACCTACAGCCTGAGCAGCACCCTGACCCTGAGCAAGGCCGACTACGAGAAGCATAAGGTGTACGCCTGCGAGGTGACCCACCAGGGCCTGTCCAGCCCCGTGA CCAAGAGCTTCAACAGGGGCGAGTGCCombined CDR Consensus sequences SEQ ID NO: 347 HCDR1 GFTFXSAAVHSEQ ID NO: 348 HCDR2 RIKSKAXGGTTDYAAPVKG SEQ ID NO: 349 HCDR2RIKSKXXGGTTDYAAPVKG SEQ ID NO: 357 HCDR2 RIKSKAXXGTTDYAAPVKGSEQ ID NO: 358 HCDR2 RIKSKXXXGTTDYAAPVKG SEQ ID NO: 350 HCDR3DSPSISSYSIPYFSGMDV SEQ ID NO: 351 LCDR1 RASQGIRAWLN SEQ ID NO: 352 LCDR1RASQXIXXXLN SEQ ID NO: 353 LCDR2 AASSLQS SEQ ID NO: 359 LCDR2 AASXLQSSEQ ID NO: 354 LCDR3 HQYITHPPT SEQ ID NO: 355 LCDR3 HQYIXXPXT Kabat CDRConsensus sequences SEQ ID NO: 356 HCDR1 SAAVH SEQ ID NO: 348 HCDR2RIKSKAXGGITDYAAPVKG SEQ ID NO: 349 HCDR2 RIKSKXXGGITDYAAPVKGSEQ ID NO: 357 HCDR2 RIKSKAXXGTTDYAAPVKG SEQ ID NO: 358 HCDR2RIKSKXXXGTTDYAAPVKG SEQ ID NO: 350 HCDR3 DSPSISSYSIPYFSGMDVSEQ ID NO: 351 LCDR1 RASQGIRAWLN SEQ ID NO: 352 LCDR1 RASQXIXXXLNSEQ ID NO: 353 LCDR2 AASSLQS SEQ ID NO: 359 LCDR2 AASXLQS SEQ ID NO: 354LCDR3 HQYITHPPT SEQ ID NO: 355 LCDR3 HQYIXXPXT

The terms “complementarity determining region,” and “CDR,” as usedherein refer to the sequences of amino acids within antibody variableregions which confer antigen specificity and binding affinity. Ingeneral, there are three CDRs in each heavy chain variable region(HCDR1, HCDR2, HCDR3) and three CDRs in each light chain variable region(LCDR1, LCDR2, LCDR3).

The precise amino acid sequence boundaries of a given CDR can be readilydetermined using any of a number of well-known schemes, including thosedescribed by Kabat et al. (1991), “Sequences of Proteins ofImmunological Interest,” 5th Ed. Public Health Service, NationalInstitutes of Health, Bethesda, Md. (“Kabat” numbering scheme),Al-Lazikani et al., (1997) JMB 273,927-948 (“Chothia” numbering scheme),or Lefranc et al., (2003) Dev. Comp. Immunol., 27, 55-77 (“IMGT”numbering scheme). Other methods for delineating the CDR regions mayalternatively be used. For example, the CDR definitions of both Kabatand Chothia may be combined (“Combined” system).

For example, under Kabat, the CDR amino acid residues of an antibody inthe heavy chain variable domain (VH) are numbered 31-35 (HCDR1), 50-66(HCDR2), and 99-111 (HCDR3); and the CDR amino acid residues in thelight chain variable domain (VL) are numbered 22-35 (LCDR1), 51-57(LCDR2), and 90-100 (LCDR3). Under Chothia the CDR amino acids in the VHare numbered 26-32 (HCDR1), 52-57 (HCDR2), and 99-111 (HCDR3); and theamino acid residues in VL are numbered 25-33 (LCDR1), 51-53 (LCDR2), and92-99 (LCDR3). By combining the CDR definitions of both Kabat andChothia, the “Combined” CDRs consist of amino acid residues 26-35(HCDR1), 50-66 (HCDR2), and 99-108 (HCDR3) in human VH and amino acidresidues 24-38 (LCDR1), 54-60 (LCDR2), and 93-101 (LCDR3) in human VL.As another example, under IMGT, the CDR amino acid residues in the heavychain variable domain (VH) are numbered 26-33 (HCDR1), 51-58 (HCDR2),and 97-108 (HCDR3); and the CDR amino acid residues in the light chainvariable domain (VL) are numbered 27-36 (LCDR1), 54-56 (LCDR2), and93-101 (LCDR3). Table 2 provides exemplary Kabat, Chothia, Combined, andIMGT HCDR1, HCDR2, HCDR3, LCDR1, LCDR2, and LCDR3 for anti-FXI/FXIaantibody binding agents (e.g., antibodies), e.g., IDT1-IDT10.

Since each of the antibodies disclosed in Table 2, can bind toanti-FXI/FXIa antibody NOV1401, and antigen-binding specificity isprovided primarily by the CDR1, 2 and 3 regions, the VH CDR1, 2 and 3sequences and VL CDR1, 2 and 3 sequences can be “mixed and matched”(i.e., CDRs from different antibodies can be mixed and matched),although each antibody preferably contains a VH CDR1, 2 and 3 and a VLCDR1, 2 and 3 to create other FXI and/or FXIa binding molecules providedherein. Such “mixed and matched” anti-FXI/FXIa antibody binding agentscan be tested using the binding assays known in the art and thosedescribed in the Examples (e.g., ELISAs, SET, BIACORE™ assays). When VHCDR sequences are mixed and matched, the CDR1, CDR2 and/or CDR3 sequencefrom a particular VH sequence should be replaced with a structurallysimilar CDR sequence(s). Likewise, when VL CDR sequences are mixed andmatched, the CDR1, CDR2 and/or CDR3 sequence from a particular VLsequence should be replaced with a structurally similar CDR sequence(s).It will be readily apparent to the ordinarily skilled artisan that novelVH and VL sequences can be created by substituting one or more VH and/orVL CDR region sequences with structurally similar sequences from the CDRsequences shown herein for antibodies provided herein. In addition tothe foregoing, in one aspect, binding agents provided herein may beantigen-binding fragments of antibodies and can comprise a VH CDR1, 2,and 3, or a VL CDR 1, 2, and 3, wherein the fragment binds to ananti-FXI/FXIa antibody, such as NOV1401, as a single variable domain.

In particular aspects, provided herein is a binding agent (e.g.,anti-idiotype antibody and fragments thereof, such as Fab fragment)which specifically binds a target anti-FXI/FXIa antibody, wherein thebinding agent inhibits an anticoagulant activity of the targetanti-FXI/FXIa antibody, wherein the target anti-FXI/FXIa antibody isantibody NOV1401(comprising a VH comprising the amino acid sequence ofSEQ ID NO: 12 and a VL comprising the amino acid sequence of SEQ ID NO:23), and wherein the binding agent is an antibody or antigen-bindingfragment thereof comprising (1) a VH comprising complementaritydetermining regions HCDR1, HCDR2, and HCDR3, and (2) a VL comprisingcomplementarity determining regions LCDR1, LCDR2, and LCDR3; wherein:

-   -   a. the HCDR1 comprises the amino acid sequence of SEQ ID NO: 27,        59, 91, 123, 155, 187, 219, 251, 283, or 315;    -   b. the HCDR2 comprises the amino acid sequence of SEQ ID NO: 28,        60, 92, 124, 156, 188, 220, 252, 284, or 316;    -   c. the HCDR3 comprises the amino acid sequence of SEQ ID NO: 29,        61, 93, 125, 157, 189, 221, 253, 285, or 317;    -   d. the LCDR1 comprises the amino acid sequence of SEQ ID NO: 43,        75, 107, 139, 171, 203, 235, 267, 299, or 331;    -   e. the LCDR2 comprises the amino acid sequence of SEQ ID NO: 44,        76, 108, 140, 172, 204, 236, 268, 300, or 332; and    -   f. the LCDR3 comprises the amino acid sequence of SEQ ID NO: 45,        77, 109, 141, 173, 205, 237, 269, 301, or 333.

In particular aspects, provided herein is a binding agent (e.g.,anti-idiotype antibody and fragments thereof, such as Fab fragment)which specifically binds a target anti-FXI/FXIa antibody, wherein thebinding agent inhibits an anticoagulant activity of the targetanti-FXI/FXIa antibody, wherein the target anti-FXI/FXIa antibody isantibody NOV1401(comprising a VH comprising the amino acid sequence ofSEQ ID NO: 12 and a VL comprising the amino acid sequence of SEQ ID NO:23), and wherein the binding agent is an antibody or antigen-bindingfragment thereof comprising (1) a VH comprising complementaritydetermining regions HCDR1, HCDR2, and HCDR3, and (2) a VL comprisingcomplementarity determining regions LCDR1, LCDR2, and LCDR3; wherein:

-   -   a. the HCDR1 comprises the amino acid sequence of SEQ ID NO: 30,        62, 94, 126, 158, 190, 222, 254, 286, or 318;    -   b. the HCDR2 comprises the amino acid sequence of SEQ ID NO: 31,        63, 95, 127, 159, 191, 223, 255, 287, or 319;    -   c. the HCDR3 comprises the amino acid sequence of SEQ ID NO: 32,        64, 96, 128, 160, 192, 224, 256, 288, or 320;    -   d. the LCDR1 comprises the amino acid sequence of SEQ ID NO: 46,        78, 110, 142, 174, 206, 238, 270, 302, or 334;    -   e. the LCDR2 comprises the amino acid sequence of SEQ ID NO: 47,        79, 111, 143, 175, 207, 239, 271, 303, or 335; and    -   f. the LCDR3 comprises the amino acid sequence of SEQ ID NO: 48,        80, 112, 144, 176, 208, 240, 272, 304, or 336.

In particular aspects, provided herein is a binding agent (e.g.,anti-idiotype antibody and fragments thereof, such as Fab fragment)which specifically binds a target anti-FXI/FXIa antibody, wherein thebinding agent inhibits an anticoagulant activity of the targetanti-FXI/FXIa antibody, wherein the target anti-FXI/FXIa antibody isantibody NOV1401(comprising a VH comprising the amino acid sequence ofSEQ ID NO: 12 and a VL comprising the amino acid sequence of SEQ ID NO:23), and wherein the binding agent is an antibody or antigen-bindingfragment thereof comprising (1) a VH comprising complementaritydetermining regions HCDR1, HCDR2, and HCDR3, and (2) a VL comprisingcomplementarity determining regions LCDR1, LCDR2, and LCDR3; wherein

-   -   a. the HCDR1 comprises the amino acid sequence GFTF-X1-SAAVH        (SEQ ID NO: 347), wherein X1 is any amino acid or is S or Q;    -   b. the HCDR2 comprises the amino acid sequence        RIKSKA-X4-X5-GTTDYAAPVKG (SEQ ID NO: 357),        RIKSK-X3-X4-X5-GTTDYAAPVKG (SEQ ID NO: 358),        RIKSK-X3-X4-GGTTDYAAPVKG (SEQ ID NO: 349) or        RIKSKA-X4-GGTTDYAAPVKG (SEQ ID NO: 348), wherein X3 is any amino        acid or is T or A, X4 is any amino acid or is S or D, and X5 is        any amino acid or is G or A;    -   c. the HCDR3 comprises the amino acid sequence        DSPSISSYSIPYFSGMDV (SEQ ID NO: 350);    -   d. the LCDR1 comprises the amino acid sequence RASQGIRAWLN (SEQ        ID NO: 351) or RASQ-X6-I-X7-X8-X9-LN (SEQ ID NO: 352), wherein        X6 is any amino acid or is S or G, X7 is any amino acid or is R        or S, X8 is any amino acid or is A or N, and X9 is any amino        acid or is W or Y;    -   e. the LCDR2 comprises the amino acid sequence AASSLQS (SEQ ID        NO: 353); and    -   f. the LCDR3 comprises the amino acid sequence HQYITHPPT (SEQ ID        NO: 354) or HQYI-X10-X11-P-X12-T (SEQ ID NO: 355), wherein X10        is any amino acid or is T or A, X11 is any amino acid or is H or        K, and X12 is any amino acid or is P or I.

In particular aspects, provided herein is a binding agent (e.g.,anti-idiotype antibody and fragments thereof, such as Fab fragment)which specifically binds a target anti-FXI/FXIa antibody, wherein thebinding agent inhibits an anticoagulant activity of the targetanti-FXI/FXIa antibody, wherein the target anti-FXI/FXIa antibody isantibody NOV1401(comprising a VH comprising the amino acid sequence ofSEQ ID NO: 12 and a VL comprising the amino acid sequence of SEQ ID NO:23), and wherein the binding agent is an antibody or antigen-bindingfragment thereof comprising (1) a VH comprising complementaritydetermining regions HCDR1, HCDR2, and HCDR3, and (2) a VL comprisingcomplementarity determining regions LCDR1, LCDR2, and LCDR3; wherein

-   -   a. the HCDR1 comprises the amino acid sequence GFTF-X1-SAAVH        (SEQ ID NO: 347), wherein X1 is S or Q;    -   b. the HCDR2 comprises the amino acid sequence        RIKSKA-X4-X5-GTTDYAAPVKG (SEQ ID NO: 357), wherein X4 is S or D        and X5 is G or A;    -   c. the HCDR3 comprises the amino acid sequence        DSPSISSYSIPYFSGMDV (SEQ ID NO: 350);    -   d. the LCDR1 comprises the amino acid sequence RASQGIRAWLN (SEQ        ID NO: 351);    -   e. the LCDR2 comprises the amino acid sequence AASSLQS (SEQ ID        NO: 353); and    -   f. the LCDR3 comprises the amino acid sequence HQYITHPPT (SEQ ID        NO: 354).

In particular aspects, provided herein is a binding agent (e.g.,anti-idiotype antibody and fragments thereof, such as Fab fragment)which specifically binds a target anti-FXI/FXIa antibody, wherein thebinding agent inhibits an anticoagulant activity of the targetanti-FXI/FXIa antibody, wherein the target anti-FXI/FXIa antibody isantibody NOV1401(comprising a VH comprising the amino acid sequence ofSEQ ID NO: 12 and a VL comprising the amino acid sequence of SEQ ID NO:23), and wherein the binding agent is an antibody or antigen-bindingfragment thereof comprising (1) a VH comprising complementaritydetermining regions HCDR1, HCDR2, and HCDR3, and (2) a VL comprisingcomplementarity determining regions LCDR1, LCDR2, and LCDR3; wherein

-   -   a. the HCDR1 comprises the amino acid sequence SAAVH (SEQ ID NO:        356);    -   b. the HCDR2 comprises the amino acid sequence        RIKSKA-X4-X5-GTTDYAAPVKG (SEQ ID NO: 357),        RIKSK-X3-X4-X5-GTTDYAAPVKG (SEQ ID NO: 358),        RIKSK-X3-X4-GGTTDYAAPVKG (SEQ ID NO: 349) or        RIKSKA-X4-GGTTDYAAPVKG (SEQ ID NO: 348), wherein X3 is any amino        acid or is T or A, X4 is any amino acid or is S or D, and X5 is        any amino acid or is G or A;    -   c. the HCDR3 comprises the amino acid sequence        DSPSISSYSIPYFSGMDV (SEQ ID NO: 350);    -   d. the LCDR1 comprises the amino acid sequence RASQGIRAWLN (SEQ        ID NO: 351) or RASQ-X6-I-X7-X8-X9-LN (SEQ ID NO: 352), wherein        X6 is any amino acid or is S or G, X7 is any amino acid or is R        or S, X8 is any amino acid or is A or N, and X9 is any amino        acid or is W or Y;    -   e. the LCDR2 comprises the amino acid sequence AASSLQS (SEQ ID        NO: 353); and    -   f. the LCDR3 comprises the amino acid sequence HQYITHPPT (SEQ ID        NO: 354) or HQYI-X10-X11-P-X12-T (SEQ ID NO: 355), wherein X10        is any amino acid or is T or A, X11 is any amino acid or is H or        K, and X12 is any amino acid or is P or I.

In particular aspects, provided herein is a binding agent (e.g.,anti-idiotype antibody and fragments thereof, such as Fab fragment)which specifically binds a target anti-FXI/FXIa antibody, wherein thebinding agent inhibits an anticoagulant activity of the targetanti-FXI/FXIa antibody, wherein the target anti-FXI/FXIa antibody isantibody NOV1401(comprising a VH comprising the amino acid sequence ofSEQ ID NO: 12 and a VL comprising the amino acid sequence of SEQ ID NO:23), wherein the binding agent is an antibody or antigen-bindingfragment thereof comprising (1) a VH comprising complementaritydetermining regions HCDR1, HCDR2, and HCDR3, and (2) a VL comprisingcomplementarity determining regions LCDR1, LCDR2, and LCDR3; wherein

-   -   a. the HCDR1 comprises the amino acid sequence SAAVH (SEQ ID NO:        356);    -   b. the HCDR2 comprises the amino acid sequence        RIKSKA-X4-X5-GTTDYAAPVKG (SEQ ID NO: 357), wherein X4 is S or D        and X5 is G or A;    -   c. the HCDR3 comprises the amino acid sequence        DSPSISSYSIPYFSGMDV (SEQ ID NO: 350);    -   d. the LCDR1 comprises the amino acid sequence RASQGIRAWLN (SEQ        ID NO: 351);    -   e. the LCDR2 comprises the amino acid sequence AASSLQS (SEQ ID        NO: 353); and    -   f. the LCDR3 comprises the amino acid sequence HQYITHPPT (SEQ ID        NO: 354).

In particular aspects, provided herein is a binding agent (e.g.,anti-idiotype antibody and fragments thereof, such as Fab fragment)which specifically binds a target anti-FXI/FXIa antibody (e.g., NOV1401comprising a VH comprising the amino acid sequence of SEQ ID NO: 12 anda VL comprising the amino acid sequence of SEQ ID NO: 23), wherein thebinding agent inhibits an anticoagulant activity of the targetanti-FXI/FXIa antibody, wherein the binding agent is an antibody orantigen-binding fragment thereof comprising (1) a VH comprisingcomplementarity determining regions HCDR1, HCDR2, and HCDR3, and (2) aVL comprising complementarity determining regions LCDR1, LCDR2, andLCDR3; wherein the HCDR1 comprises the amino acid sequence of SEQ ID NO:91, the HCDR2 comprises the amino acid sequence of SEQ ID NO: 92, theHCDR3 comprises the amino acid sequence of SEQ ID NO: 93, the LCDR1comprises the amino acid sequence of SEQ ID NO: 107, the LCDR2 comprisesthe amino acid sequence of SEQ ID NO: 108, and the LCDR3 comprises theamino acid sequence of SEQ ID NO: 109.

In particular aspects, provided herein is a binding agent (e.g.,anti-idiotype antibody and fragments thereof, such as Fab fragment)which specifically binds a target anti-FXI/FXIa antibody (e.g., NOV1401comprising a VH comprising the amino acid sequence of SEQ ID NO: 12 anda VL comprising the amino acid sequence of SEQ ID NO: 23), wherein thebinding agent inhibits an anticoagulant activity of the targetanti-FXI/FXIa antibody, wherein the binding agent is an antibody orantigen-binding fragment thereof comprising (1) a VH comprisingcomplementarity determining regions HCDR1, HCDR2, and HCDR3, and (2) aVL comprising complementarity determining regions LCDR1, LCDR2, andLCDR3; wherein the HCDR1 comprises the amino acid sequence of SEQ ID NO:94, the HCDR2 comprises the amino acid sequence of SEQ ID NO: 95, theHCDR3 comprises the amino acid sequence of SEQ ID NO: 96, the LCDR1comprises the amino acid sequence of SEQ ID NO: 110, the LCDR2 comprisesthe amino acid sequence of SEQ ID NO: 111, and the LCDR3 comprises theamino acid sequence of SEQ ID NO: 112.

In particular aspects, provided herein is a binding agent (e.g.,anti-idiotype antibody and fragments thereof, such as Fab fragment)which specifically binds a target anti-FXI/FXIa antibody (e.g., NOV1401comprising a VH comprising the amino acid sequence of SEQ ID NO: 12 anda VL comprising the amino acid sequence of SEQ ID NO: 23), wherein thebinding agent inhibits an anticoagulant activity of the targetanti-FXI/FXIa antibody, wherein the binding agent is an antibody orantigen-binding fragment thereof comprising (1) a VH comprisingcomplementarity determining regions HCDR1, HCDR2, and HCDR3, and (2) aVL comprising complementarity determining regions LCDR1, LCDR2, andLCDR3; wherein the HCDR1 comprises the amino acid sequence of SEQ ID NO:97, the HCDR2 comprises the amino acid sequence of SEQ ID NO: 98, theHCDR3 comprises the amino acid sequence of SEQ ID NO: 99, the LCDR1comprises the amino acid sequence of SEQ ID NO: 113, the LCDR2 comprisesthe amino acid sequence of SEQ ID NO: 114, and the LCDR3 comprises theamino acid sequence of SEQ ID NO: 115.

In particular aspects, provided herein is a binding agent (e.g.,anti-idiotype antibody and fragments thereof, such as Fab fragment)which specifically binds a target anti-FXI/FXIa antibody (e.g., NOV1401comprising a VH comprising the amino acid sequence of SEQ ID NO: 12 anda VL comprising the amino acid sequence of SEQ ID NO: 23), wherein thebinding agent inhibits an anticoagulant activity of the targetanti-FXI/FXIa antibody, wherein the binding agent is an antibody orantigen-binding fragment thereof comprising (1) a VH comprisingcomplementarity determining regions HCDR1, HCDR2, and HCDR3, and (2) aVL comprising complementarity determining regions LCDR1, LCDR2, andLCDR3; wherein the HCDR1 comprises the amino acid sequence of SEQ ID NO:100, the HCDR2 comprises the amino acid sequence of SEQ ID NO: 101, theHCDR3 comprises the amino acid sequence of SEQ ID NO: 102, the LCDR1comprises the amino acid sequence of SEQ ID NO: 116, the LCDR2 comprisesthe amino acid sequence of SEQ ID NO: 117, and the LCDR3 comprises theamino acid sequence of SEQ ID NO: 118.

In particular aspects, provided herein is a binding agent (e.g.,anti-idiotype antibody and fragments thereof, such as Fab fragment)which specifically binds a target anti-FXI/FXIa antibody (e.g., NOV1401comprising a VH comprising the amino acid sequence of SEQ ID NO: 12 anda VL comprising the amino acid sequence of SEQ ID NO: 23), wherein thebinding agent inhibits an anticoagulant activity of the targetanti-FXI/FXIa antibody, wherein the binding agent is an antibody orantigen-binding fragment thereof comprising (1) a VH comprisingcomplementarity determining regions HCDR1, HCDR2, and HCDR3, and (2) aVL comprising complementarity determining regions LCDR1, LCDR2, andLCDR3; wherein the HCDR1 comprises the amino acid sequence of SEQ ID NO:27, the HCDR2 comprises the amino acid sequence of SEQ ID NO: 28, theHCDR3 comprises the amino acid sequence of SEQ ID NO: 29, the LCDR1comprises the amino acid sequence of SEQ ID NO: 43, the LCDR2 comprisesthe amino acid sequence of SEQ ID NO: 44, and the LCDR3 comprises theamino acid sequence of SEQ ID NO: 45.

In particular aspects, provided herein is a binding agent (e.g.,anti-idiotype antibody and fragments thereof, such as Fab fragment)which specifically binds a target anti-FXI/FXIa antibody (e.g., NOV1401comprising a VH comprising the amino acid sequence of SEQ ID NO: 12 anda VL comprising the amino acid sequence of SEQ ID NO: 23), wherein thebinding agent inhibits an anticoagulant activity of the targetanti-FXI/FXIa antibody, wherein the binding agent is an antibody orantigen-binding fragment thereof comprising (1) a VH comprisingcomplementarity determining regions HCDR1, HCDR2, and HCDR3, and (2) aVL comprising complementarity determining regions LCDR1, LCDR2, andLCDR3; wherein the HCDR1 comprises the amino acid sequence of SEQ ID NO:30, the HCDR2 comprises the amino acid sequence of SEQ ID NO: 31, theHCDR3 comprises the amino acid sequence of SEQ ID NO: 32, the LCDR1comprises the amino acid sequence of SEQ ID NO: 46, the LCDR2 comprisesthe amino acid sequence of SEQ ID NO: 47, and the LCDR3 comprises theamino acid sequence of SEQ ID NO: 48.

In particular aspects, provided herein is a binding agent (e.g.,anti-idiotype antibody and fragments thereof, such as Fab fragment)which specifically binds a target anti-FXI/FXIa antibody (e.g., NOV1401comprising a VH comprising the amino acid sequence of SEQ ID NO: 12 anda VL comprising the amino acid sequence of SEQ ID NO: 23), wherein thebinding agent inhibits an anticoagulant activity of the targetanti-FXI/FXIa antibody, wherein the binding agent is an antibody orantigen-binding fragment thereof comprising (1) a VH comprisingcomplementarity determining regions HCDR1, HCDR2, and HCDR3, and (2) aVL comprising complementarity determining regions LCDR1, LCDR2, andLCDR3; wherein the HCDR1 comprises the amino acid sequence of SEQ ID NO:33, the HCDR2 comprises the amino acid sequence of SEQ ID NO: 34, theHCDR3 comprises the amino acid sequence of SEQ ID NO: 35, the LCDR1comprises the amino acid sequence of SEQ ID NO: 49, the LCDR2 comprisesthe amino acid sequence of SEQ ID NO: 50, and the LCDR3 comprises theamino acid sequence of SEQ ID NO: 51.

In particular aspects, provided herein is a binding agent (e.g.,anti-idiotype antibody and fragments thereof, such as Fab fragment)which specifically binds a target anti-FXI/FXIa antibody (e.g., NOV1401comprising a VH comprising the amino acid sequence of SEQ ID NO: 12 anda VL comprising the amino acid sequence of SEQ ID NO: 23), wherein thebinding agent inhibits an anticoagulant activity of the targetanti-FXI/FXIa antibody, wherein the binding agent is an antibody orantigen-binding fragment thereof comprising (1) a VH comprisingcomplementarity determining regions HCDR1, HCDR2, and HCDR3, and (2) aVL comprising complementarity determining regions LCDR1, LCDR2, andLCDR3; wherein the HCDR1 comprises the amino acid sequence of SEQ ID NO:36, the HCDR2 comprises the amino acid sequence of SEQ ID NO: 37, theHCDR3 comprises the amino acid sequence of SEQ ID NO: 38, the LCDR1comprises the amino acid sequence of SEQ ID NO: 52, the LCDR2 comprisesthe amino acid sequence of SEQ ID NO: 53, and the LCDR3 comprises theamino acid sequence of SEQ ID NO: 54.

In particular aspects, provided herein is a binding agent (e.g.,anti-idiotype antibody and fragments thereof, such as Fab fragment)which specifically binds a target anti-FXI/FXIa antibody (e.g., NOV1401comprising a VH comprising the amino acid sequence of SEQ ID NO: 12 anda VL comprising the amino acid sequence of SEQ ID NO: 23), wherein thebinding agent inhibits an anticoagulant activity of the targetanti-FXI/FXIa antibody, wherein the binding agent is an antibody orantigen-binding fragment thereof comprising (1) a VH comprisingcomplementarity determining regions HCDR1, HCDR2, and HCDR3, and (2) aVL comprising complementarity determining regions LCDR1, LCDR2, andLCDR3; wherein the HCDR1 comprises the amino acid sequence of SEQ ID NO:59, the HCDR2 comprises the amino acid sequence of SEQ ID NO: 60, theHCDR3 comprises the amino acid sequence of SEQ ID NO: 61, the LCDR1comprises the amino acid sequence of SEQ ID NO: 75, the LCDR2 comprisesthe amino acid sequence of SEQ ID NO: 76, and the LCDR3 comprises theamino acid sequence of SEQ ID NO: 77.

In particular aspects, provided herein is a binding agent (e.g.,anti-idiotype antibody and fragments thereof, such as Fab fragment)which specifically binds a target anti-FXI/FXIa antibody (e.g., NOV1401comprising a VH comprising the amino acid sequence of SEQ ID NO: 12 anda VL comprising the amino acid sequence of SEQ ID NO: 23), wherein thebinding agent inhibits an anticoagulant activity of the targetanti-FXI/FXIa antibody, wherein the binding agent is an antibody orantigen-binding fragment thereof comprising (1) a VH comprisingcomplementarity determining regions HCDR1, HCDR2, and HCDR3, and (2) aVL comprising complementarity determining regions LCDR1, LCDR2, andLCDR3; wherein the HCDR1 comprises the amino acid sequence of SEQ ID NO:62, the HCDR2 comprises the amino acid sequence of SEQ ID NO: 63, theHCDR3 comprises the amino acid sequence of SEQ ID NO: 64, the LCDR1comprises the amino acid sequence of SEQ ID NO: 78, the LCDR2 comprisesthe amino acid sequence of SEQ ID NO: 79, and the LCDR3 comprises theamino acid sequence of SEQ ID NO: 80.

In particular aspects, provided herein is a binding agent (e.g.,anti-idiotype antibody and fragments thereof, such as Fab fragment)which specifically binds a target anti-FXI/FXIa antibody (e.g., NOV1401comprising a VH comprising the amino acid sequence of SEQ ID NO: 12 anda VL comprising the amino acid sequence of SEQ ID NO: 23), wherein thebinding agent inhibits an anticoagulant activity of the targetanti-FXI/FXIa antibody, wherein the binding agent is an antibody orantigen-binding fragment thereof comprising (1) a VH comprisingcomplementarity determining regions HCDR1, HCDR2, and HCDR3, and (2) aVL comprising complementarity determining regions LCDR1, LCDR2, andLCDR3; wherein the HCDR1 comprises the amino acid sequence of SEQ ID NO:65, the HCDR2 comprises the amino acid sequence of SEQ ID NO: 66, theHCDR3 comprises the amino acid sequence of SEQ ID NO: 67, the LCDR1comprises the amino acid sequence of SEQ ID NO: 81, the LCDR2 comprisesthe amino acid sequence of SEQ ID NO: 82, and the LCDR3 comprises theamino acid sequence of SEQ ID NO: 83.

In particular aspects, provided herein is a binding agent (e.g.,anti-idiotype antibody and fragments thereof, such as Fab fragment)which specifically binds a target anti-FXI/FXIa antibody (e.g., NOV1401comprising a VH comprising the amino acid sequence of SEQ ID NO: 12 anda VL comprising the amino acid sequence of SEQ ID NO: 23), wherein thebinding agent inhibits an anticoagulant activity of the targetanti-FXI/FXIa antibody, wherein the binding agent is an antibody orantigen-binding fragment thereof comprising (1) a VH comprisingcomplementarity determining regions HCDR1, HCDR2, and HCDR3, and (2) aVL comprising complementarity determining regions LCDR1, LCDR2, andLCDR3; wherein the HCDR1 comprises the amino acid sequence of SEQ ID NO:68, the HCDR2 comprises the amino acid sequence of SEQ ID NO: 69, theHCDR3 comprises the amino acid sequence of SEQ ID NO: 70, the LCDR1comprises the amino acid sequence of SEQ ID NO: 84, the LCDR2 comprisesthe amino acid sequence of SEQ ID NO: 85, and the LCDR3 comprises theamino acid sequence of SEQ ID NO: 86.

In particular aspects, provided herein is a binding agent (e.g.,anti-idiotype antibody and fragments thereof, such as Fab fragment)which specifically binds a target anti-FXI/FXIa antibody (e.g., NOV1401comprising a VH comprising the amino acid sequence of SEQ ID NO: 12 anda VL comprising the amino acid sequence of SEQ ID NO: 23), wherein thebinding agent inhibits an anticoagulant activity of the targetanti-FXI/FXIa antibody, wherein the binding agent is an antibody orantigen-binding fragment thereof comprising (1) a VH comprisingcomplementarity determining regions HCDR1, HCDR2, and HCDR3, and (2) aVL comprising complementarity determining regions LCDR1, LCDR2, andLCDR3; wherein the HCDR1 comprises the amino acid sequence of SEQ ID NO:123, the HCDR2 comprises the amino acid sequence of SEQ ID NO: 124, theHCDR3 comprises the amino acid sequence of SEQ ID NO: 125, the LCDR1comprises the amino acid sequence of SEQ ID NO: 139, the LCDR2 comprisesthe amino acid sequence of SEQ ID NO: 140, and the LCDR3 comprises theamino acid sequence of SEQ ID NO: 141.

In particular aspects, provided herein is a binding agent (e.g.,anti-idiotype antibody and fragments thereof, such as Fab fragment)which specifically binds a target anti-FXI/FXIa antibody (e.g., NOV1401comprising a VH comprising the amino acid sequence of SEQ ID NO: 12 anda VL comprising the amino acid sequence of SEQ ID NO: 23), wherein thebinding agent inhibits an anticoagulant activity of the targetanti-FXI/FXIa antibody, wherein the binding agent is an antibody orantigen-binding fragment thereof comprising (1) a VH comprisingcomplementarity determining regions HCDR1, HCDR2, and HCDR3, and (2) aVL comprising complementarity determining regions LCDR1, LCDR2, andLCDR3; wherein the HCDR1 comprises the amino acid sequence of SEQ ID NO:126, the HCDR2 comprises the amino acid sequence of SEQ ID NO: 127, theHCDR3 comprises the amino acid sequence of SEQ ID NO: 128, the LCDR1comprises the amino acid sequence of SEQ ID NO: 142, the LCDR2 comprisesthe amino acid sequence of SEQ ID NO: 143, and the LCDR3 comprises theamino acid sequence of SEQ ID NO: 144.

In particular aspects, provided herein is a binding agent (e.g.,anti-idiotype antibody and fragments thereof, such as Fab fragment)which specifically binds a target anti-FXI/FXIa antibody (e.g., NOV1401comprising a VH comprising the amino acid sequence of SEQ ID NO: 12 anda VL comprising the amino acid sequence of SEQ ID NO: 23), wherein thebinding agent inhibits an anticoagulant activity of the targetanti-FXI/FXIa antibody, wherein the binding agent is an antibody orantigen-binding fragment thereof comprising (1) a VH comprisingcomplementarity determining regions HCDR1, HCDR2, and HCDR3, and (2) aVL comprising complementarity determining regions LCDR1, LCDR2, andLCDR3; wherein the HCDR1 comprises the amino acid sequence of SEQ ID NO:129, the HCDR2 comprises the amino acid sequence of SEQ ID NO: 130, theHCDR3 comprises the amino acid sequence of SEQ ID NO: 131, the LCDR1comprises the amino acid sequence of SEQ ID NO: 145, the LCDR2 comprisesthe amino acid sequence of SEQ ID NO: 146, and the LCDR3 comprises theamino acid sequence of SEQ ID NO: 147.

In particular aspects, provided herein is a binding agent (e.g.,anti-idiotype antibody and fragments thereof, such as Fab fragment)which specifically binds a target anti-FXI/FXIa antibody (e.g., NOV1401comprising a VH comprising the amino acid sequence of SEQ ID NO: 12 anda VL comprising the amino acid sequence of SEQ ID NO: 23), wherein thebinding agent inhibits an anticoagulant activity of the targetanti-FXI/FXIa antibody, wherein the binding agent is an antibody orantigen-binding fragment thereof comprising (1) a VH comprisingcomplementarity determining regions HCDR1, HCDR2, and HCDR3, and (2) aVL comprising complementarity determining regions LCDR1, LCDR2, andLCDR3; wherein the HCDR1 comprises the amino acid sequence of SEQ ID NO:132, the HCDR2 comprises the amino acid sequence of SEQ ID NO: 133, theHCDR3 comprises the amino acid sequence of SEQ ID NO: 134, the LCDR1comprises the amino acid sequence of SEQ ID NO: 148, the LCDR2 comprisesthe amino acid sequence of SEQ ID NO: 149, and the LCDR3 comprises theamino acid sequence of SEQ ID NO: 150.

In particular aspects, provided herein is a binding agent (e.g.,anti-idiotype antibody and fragments thereof, such as Fab fragment)which specifically binds a target anti-FXI/FXIa antibody (e.g., NOV1401comprising a VH comprising the amino acid sequence of SEQ ID NO: 12 anda VL comprising the amino acid sequence of SEQ ID NO: 23), wherein thebinding agent inhibits an anticoagulant activity of the targetanti-FXI/FXIa antibody, wherein the binding agent is an antibody orantigen-binding fragment thereof comprising (1) a VH comprisingcomplementarity determining regions HCDR1, HCDR2, and HCDR3, and (2) aVL comprising complementarity determining regions LCDR1, LCDR2, andLCDR3; wherein the HCDR1 comprises the amino acid sequence of SEQ ID NO:155, the HCDR2 comprises the amino acid sequence of SEQ ID NO: 156, theHCDR3 comprises the amino acid sequence of SEQ ID NO: 157, the LCDR1comprises the amino acid sequence of SEQ ID NO: 171, the LCDR2 comprisesthe amino acid sequence of SEQ ID NO: 172, and the LCDR3 comprises theamino acid sequence of SEQ ID NO: 173.

In particular aspects, provided herein is a binding agent (e.g.,anti-idiotype antibody and fragments thereof, such as Fab fragment)which specifically binds a target anti-FXI/FXIa antibody (e.g., NOV1401comprising a VH comprising the amino acid sequence of SEQ ID NO: 12 anda VL comprising the amino acid sequence of SEQ ID NO: 23), wherein thebinding agent inhibits an anticoagulant activity of the targetanti-FXI/FXIa antibody, wherein the binding agent is an antibody orantigen-binding fragment thereof comprising (1) a VH comprisingcomplementarity determining regions HCDR1, HCDR2, and HCDR3, and (2) aVL comprising complementarity determining regions LCDR1, LCDR2, andLCDR3; wherein the HCDR1 comprises the amino acid sequence of SEQ ID NO:158, the HCDR2 comprises the amino acid sequence of SEQ ID NO: 159, theHCDR3 comprises the amino acid sequence of SEQ ID NO: 160, the LCDR1comprises the amino acid sequence of SEQ ID NO: 174, the LCDR2 comprisesthe amino acid sequence of SEQ ID NO: 175, and the LCDR3 comprises theamino acid sequence of SEQ ID NO: 176.

In particular aspects, provided herein is a binding agent (e.g.,anti-idiotype antibody and fragments thereof, such as Fab fragment)which specifically binds a target anti-FXI/FXIa antibody (e.g., NOV1401comprising a VH comprising the amino acid sequence of SEQ ID NO: 12 anda VL comprising the amino acid sequence of SEQ ID NO: 23), wherein thebinding agent inhibits an anticoagulant activity of the targetanti-FXI/FXIa antibody, wherein the binding agent is an antibody orantigen-binding fragment thereof comprising (1) a VH comprisingcomplementarity determining regions HCDR1, HCDR2, and HCDR3, and (2) aVL comprising complementarity determining regions LCDR1, LCDR2, andLCDR3; wherein the HCDR1 comprises the amino acid sequence of SEQ ID NO:161, the HCDR2 comprises the amino acid sequence of SEQ ID NO: 162, theHCDR3 comprises the amino acid sequence of SEQ ID NO: 163, the LCDR1comprises the amino acid sequence of SEQ ID NO: 177, the LCDR2 comprisesthe amino acid sequence of SEQ ID NO: 178, and the LCDR3 comprises theamino acid sequence of SEQ ID NO: 179.

In particular aspects, provided herein is a binding agent (e.g.,anti-idiotype antibody and fragments thereof, such as Fab fragment)which specifically binds a target anti-FXI/FXIa antibody (e.g., NOV1401comprising a VH comprising the amino acid sequence of SEQ ID NO: 12 anda VL comprising the amino acid sequence of SEQ ID NO: 23), wherein thebinding agent inhibits an anticoagulant activity of the targetanti-FXI/FXIa antibody, wherein the binding agent is an antibody orantigen-binding fragment thereof comprising (1) a VH comprisingcomplementarity determining regions HCDR1, HCDR2, and HCDR3, and (2) aVL comprising complementarity determining regions LCDR1, LCDR2, andLCDR3; wherein the HCDR1 comprises the amino acid sequence of SEQ ID NO:164, the HCDR2 comprises the amino acid sequence of SEQ ID NO: 165, theHCDR3 comprises the amino acid sequence of SEQ ID NO: 166, the LCDR1comprises the amino acid sequence of SEQ ID NO: 180, the LCDR2 comprisesthe amino acid sequence of SEQ ID NO: 181, and the LCDR3 comprises theamino acid sequence of SEQ ID NO: 182.

In particular aspects, provided herein is a binding agent (e.g.,anti-idiotype antibody and fragments thereof, such as Fab fragment)which specifically binds a target anti-FXI/FXIa antibody (e.g., NOV1401comprising a VH comprising the amino acid sequence of SEQ ID NO: 12 anda VL comprising the amino acid sequence of SEQ ID NO: 23), wherein thebinding agent inhibits an anticoagulant activity of the targetanti-FXI/FXIa antibody, wherein the binding agent is an antibody orantigen-binding fragment thereof comprising (1) a VH comprisingcomplementarity determining regions HCDR1, HCDR2, and HCDR3, and (2) aVL comprising complementarity determining regions LCDR1, LCDR2, andLCDR3; wherein the HCDR1 comprises the amino acid sequence of SEQ ID NO:187, the HCDR2 comprises the amino acid sequence of SEQ ID NO: 188, theHCDR3 comprises the amino acid sequence of SEQ ID NO: 189, the LCDR1comprises the amino acid sequence of SEQ ID NO: 203, the LCDR2 comprisesthe amino acid sequence of SEQ ID NO: 204, and the LCDR3 comprises theamino acid sequence of SEQ ID NO: 205.

In particular aspects, provided herein is a binding agent (e.g.,anti-idiotype antibody and fragments thereof, such as Fab fragment)which specifically binds a target anti-FXI/FXIa antibody (e.g., NOV1401comprising a VH comprising the amino acid sequence of SEQ ID NO: 12 anda VL comprising the amino acid sequence of SEQ ID NO: 23), wherein thebinding agent inhibits an anticoagulant activity of the targetanti-FXI/FXIa antibody, wherein the binding agent is an antibody orantigen-binding fragment thereof comprising (1) a VH comprisingcomplementarity determining regions HCDR1, HCDR2, and HCDR3, and (2) aVL comprising complementarity determining regions LCDR1, LCDR2, andLCDR3; wherein the HCDR1 comprises the amino acid sequence of SEQ ID NO:190, the HCDR2 comprises the amino acid sequence of SEQ ID NO: 191, theHCDR3 comprises the amino acid sequence of SEQ ID NO: 192, the LCDR1comprises the amino acid sequence of SEQ ID NO: 206, the LCDR2 comprisesthe amino acid sequence of SEQ ID NO: 207, and the LCDR3 comprises theamino acid sequence of SEQ ID NO: 208.

In particular aspects, provided herein is a binding agent (e.g.,anti-idiotype antibody and fragments thereof, such as Fab fragment)which specifically binds a target anti-FXI/FXIa antibody (e.g., NOV1401comprising a VH comprising the amino acid sequence of SEQ ID NO: 12 anda VL comprising the amino acid sequence of SEQ ID NO: 23), wherein thebinding agent inhibits an anticoagulant activity of the targetanti-FXI/FXIa antibody, wherein the binding agent is an antibody orantigen-binding fragment thereof comprising (1) a VH comprisingcomplementarity determining regions HCDR1, HCDR2, and HCDR3, and (2) aVL comprising complementarity determining regions LCDR1, LCDR2, andLCDR3; wherein the HCDR1 comprises the amino acid sequence of SEQ ID NO:193, the HCDR2 comprises the amino acid sequence of SEQ ID NO: 194, theHCDR3 comprises the amino acid sequence of SEQ ID NO: 195, the LCDR1comprises the amino acid sequence of SEQ ID NO: 209, the LCDR2 comprisesthe amino acid sequence of SEQ ID NO: 210, and the LCDR3 comprises theamino acid sequence of SEQ ID NO: 211.

In particular aspects, provided herein is a binding agent (e.g.,anti-idiotype antibody and fragments thereof, such as Fab fragment)which specifically binds a target anti-FXI/FXIa antibody (e.g., NOV1401comprising a VH comprising the amino acid sequence of SEQ ID NO: 12 anda VL comprising the amino acid sequence of SEQ ID NO: 23), wherein thebinding agent inhibits an anticoagulant activity of the targetanti-FXI/FXIa antibody, wherein the binding agent is an antibody orantigen-binding fragment thereof comprising (1) a VH comprisingcomplementarity determining regions HCDR1, HCDR2, and HCDR3, and (2) aVL comprising complementarity determining regions LCDR1, LCDR2, andLCDR3; wherein the HCDR1 comprises the amino acid sequence of SEQ ID NO:196, the HCDR2 comprises the amino acid sequence of SEQ ID NO: 197, theHCDR3 comprises the amino acid sequence of SEQ ID NO: 198, the LCDR1comprises the amino acid sequence of SEQ ID NO: 212, the LCDR2 comprisesthe amino acid sequence of SEQ ID NO: 213, and the LCDR3 comprises theamino acid sequence of SEQ ID NO: 214.

In particular aspects, provided herein is a binding agent (e.g.,anti-idiotype antibody and fragments thereof, such as Fab fragment)which specifically binds a target anti-FXI/FXIa antibody (e.g., NOV1401comprising a VH comprising the amino acid sequence of SEQ ID NO: 12 anda VL comprising the amino acid sequence of SEQ ID NO: 23), wherein thebinding agent inhibits an anticoagulant activity of the targetanti-FXI/FXIa antibody, wherein the binding agent is an antibody orantigen-binding fragment thereof comprising (1) a VH comprisingcomplementarity determining regions HCDR1, HCDR2, and HCDR3, and (2) aVL comprising complementarity determining regions LCDR1, LCDR2, andLCDR3; wherein the HCDR1 comprises the amino acid sequence of SEQ ID NO:219, the HCDR2 comprises the amino acid sequence of SEQ ID NO: 220, theHCDR3 comprises the amino acid sequence of SEQ ID NO: 221, the LCDR1comprises the amino acid sequence of SEQ ID NO: 235, the LCDR2 comprisesthe amino acid sequence of SEQ ID NO: 236, and the LCDR3 comprises theamino acid sequence of SEQ ID NO: 237.

In particular aspects, provided herein is a binding agent (e.g.,anti-idiotype antibody and fragments thereof, such as Fab fragment)which specifically binds a target anti-FXI/FXIa antibody (e.g., NOV1401comprising a VH comprising the amino acid sequence of SEQ ID NO: 12 anda VL comprising the amino acid sequence of SEQ ID NO: 23), wherein thebinding agent inhibits an anticoagulant activity of the targetanti-FXI/FXIa antibody, wherein the binding agent is an antibody orantigen-binding fragment thereof comprising (1) a VH comprisingcomplementarity determining regions HCDR1, HCDR2, and HCDR3, and (2) aVL comprising complementarity determining regions LCDR1, LCDR2, andLCDR3; wherein the HCDR1 comprises the amino acid sequence of SEQ ID NO:222, the HCDR2 comprises the amino acid sequence of SEQ ID NO: 223, theHCDR3 comprises the amino acid sequence of SEQ ID NO: 224, the LCDR1comprises the amino acid sequence of SEQ ID NO: 238, the LCDR2 comprisesthe amino acid sequence of SEQ ID NO: 239, and the LCDR3 comprises theamino acid sequence of SEQ ID NO: 240.

In particular aspects, provided herein is a binding agent (e.g.,anti-idiotype antibody and fragments thereof, such as Fab fragment)which specifically binds a target anti-FXI/FXIa antibody (e.g., NOV1401comprising a VH comprising the amino acid sequence of SEQ ID NO: 12 anda VL comprising the amino acid sequence of SEQ ID NO: 23), wherein thebinding agent inhibits an anticoagulant activity of the targetanti-FXI/FXIa antibody, wherein the binding agent is an antibody orantigen-binding fragment thereof comprising (1) a VH comprisingcomplementarity determining regions HCDR1, HCDR2, and HCDR3, and (2) aVL comprising complementarity determining regions LCDR1, LCDR2, andLCDR3; wherein the HCDR1 comprises the amino acid sequence of SEQ ID NO:225, the HCDR2 comprises the amino acid sequence of SEQ ID NO: 226, theHCDR3 comprises the amino acid sequence of SEQ ID NO: 227, the LCDR1comprises the amino acid sequence of SEQ ID NO: 241, the LCDR2 comprisesthe amino acid sequence of SEQ ID NO: 242, and the LCDR3 comprises theamino acid sequence of SEQ ID NO: 243.

In particular aspects, provided herein is a binding agent (e.g.,anti-idiotype antibody and fragments thereof, such as Fab fragment)which specifically binds a target anti-FXI/FXIa antibody (e.g., NOV1401comprising a VH comprising the amino acid sequence of SEQ ID NO: 12 anda VL comprising the amino acid sequence of SEQ ID NO: 23), wherein thebinding agent inhibits an anticoagulant activity of the targetanti-FXI/FXIa antibody, wherein the binding agent is an antibody orantigen-binding fragment thereof comprising (1) a VH comprisingcomplementarity determining regions HCDR1, HCDR2, and HCDR3, and (2) aVL comprising complementarity determining regions LCDR1, LCDR2, andLCDR3; wherein the HCDR1 comprises the amino acid sequence of SEQ ID NO:228, the HCDR2 comprises the amino acid sequence of SEQ ID NO: 229, theHCDR3 comprises the amino acid sequence of SEQ ID NO: 230, the LCDR1comprises the amino acid sequence of SEQ ID NO: 244, the LCDR2 comprisesthe amino acid sequence of SEQ ID NO: 245, and the LCDR3 comprises theamino acid sequence of SEQ ID NO: 246.

In particular aspects, provided herein is a binding agent (e.g.,anti-idiotype antibody and fragments thereof, such as Fab fragment)which specifically binds a target anti-FXI/FXIa antibody (e.g., NOV1401comprising a VH comprising the amino acid sequence of SEQ ID NO: 12 anda VL comprising the amino acid sequence of SEQ ID NO: 23), wherein thebinding agent inhibits an anticoagulant activity of the targetanti-FXI/FXIa antibody, wherein the binding agent is an antibody orantigen-binding fragment thereof comprising (1) a VH comprisingcomplementarity determining regions HCDR1, HCDR2, and HCDR3, and (2) aVL comprising complementarity determining regions LCDR1, LCDR2, andLCDR3; wherein the HCDR1 comprises the amino acid sequence of SEQ ID NO:251, the HCDR2 comprises the amino acid sequence of SEQ ID NO: 252, theHCDR3 comprises the amino acid sequence of SEQ ID NO: 253, the LCDR1comprises the amino acid sequence of SEQ ID NO: 267, the LCDR2 comprisesthe amino acid sequence of SEQ ID NO: 268, and the LCDR3 comprises theamino acid sequence of SEQ ID NO: 269.

In particular aspects, provided herein is a binding agent (e.g.,anti-idiotype antibody and fragments thereof, such as Fab fragment)which specifically binds a target anti-FXI/FXIa antibody (e.g., NOV1401comprising a VH comprising the amino acid sequence of SEQ ID NO: 12 anda VL comprising the amino acid sequence of SEQ ID NO: 23), wherein thebinding agent inhibits an anticoagulant activity of the targetanti-FXI/FXIa antibody, wherein the binding agent is an antibody orantigen-binding fragment thereof comprising (1) a VH comprisingcomplementarity determining regions HCDR1, HCDR2, and HCDR3, and (2) aVL comprising complementarity determining regions LCDR1, LCDR2, andLCDR3; wherein the HCDR1 comprises the amino acid sequence of SEQ ID NO:254, the HCDR2 comprises the amino acid sequence of SEQ ID NO: 255, theHCDR3 comprises the amino acid sequence of SEQ ID NO: 256, the LCDR1comprises the amino acid sequence of SEQ ID NO: 270, the LCDR2 comprisesthe amino acid sequence of SEQ ID NO: 271, and the LCDR3 comprises theamino acid sequence of SEQ ID NO: 272.

In particular aspects, provided herein is a binding agent (e.g.,anti-idiotype antibody and fragments thereof, such as Fab fragment)which specifically binds a target anti-FXI/FXIa antibody (e.g., NOV1401comprising a VH comprising the amino acid sequence of SEQ ID NO: 12 anda VL comprising the amino acid sequence of SEQ ID NO: 23), wherein thebinding agent inhibits an anticoagulant activity of the targetanti-FXI/FXIa antibody, wherein the binding agent is an antibody orantigen-binding fragment thereof comprising (1) a VH comprisingcomplementarity determining regions HCDR1, HCDR2, and HCDR3, and (2) aVL comprising complementarity determining regions LCDR1, LCDR2, andLCDR3; wherein the HCDR1 comprises the amino acid sequence of SEQ ID NO:257, the HCDR2 comprises the amino acid sequence of SEQ ID NO: 258, theHCDR3 comprises the amino acid sequence of SEQ ID NO: 259, the LCDR1comprises the amino acid sequence of SEQ ID NO: 273, the LCDR2 comprisesthe amino acid sequence of SEQ ID NO: 274, and the LCDR3 comprises theamino acid sequence of SEQ ID NO: 275.

In particular aspects, provided herein is a binding agent (e.g.,anti-idiotype antibody and fragments thereof, such as Fab fragment)which specifically binds a target anti-FXI/FXIa antibody (e.g., NOV1401comprising a VH comprising the amino acid sequence of SEQ ID NO: 12 anda VL comprising the amino acid sequence of SEQ ID NO: 23), wherein thebinding agent inhibits an anticoagulant activity of the targetanti-FXI/FXIa antibody, wherein the binding agent is an antibody orantigen-binding fragment thereof comprising (1) a VH comprisingcomplementarity determining regions HCDR1, HCDR2, and HCDR3, and (2) aVL comprising complementarity determining regions LCDR1, LCDR2, andLCDR3; wherein the HCDR1 comprises the amino acid sequence of SEQ ID NO:260, the HCDR2 comprises the amino acid sequence of SEQ ID NO: 261, theHCDR3 comprises the amino acid sequence of SEQ ID NO: 262, the LCDR1comprises the amino acid sequence of SEQ ID NO: 276, the LCDR2 comprisesthe amino acid sequence of SEQ ID NO: 277, and the LCDR3 comprises theamino acid sequence of SEQ ID NO: 278.

In particular aspects, provided herein is a binding agent (e.g.,anti-idiotype antibody and fragments thereof, such as Fab fragment)which specifically binds a target anti-FXI/FXIa antibody (e.g., NOV1401comprising a VH comprising the amino acid sequence of SEQ ID NO: 12 anda VL comprising the amino acid sequence of SEQ ID NO: 23), wherein thebinding agent inhibits an anticoagulant activity of the targetanti-FXI/FXIa antibody, wherein the binding agent is an antibody orantigen-binding fragment thereof comprising (1) a VH comprisingcomplementarity determining regions HCDR1, HCDR2, and HCDR3, and (2) aVL comprising complementarity determining regions LCDR1, LCDR2, andLCDR3; wherein the HCDR1 comprises the amino acid sequence of SEQ ID NO:283, the HCDR2 comprises the amino acid sequence of SEQ ID NO: 284, theHCDR3 comprises the amino acid sequence of SEQ ID NO: 285, the LCDR1comprises the amino acid sequence of SEQ ID NO: 299, the LCDR2 comprisesthe amino acid sequence of SEQ ID NO: 300, and the LCDR3 comprises theamino acid sequence of SEQ ID NO: 301.

In particular aspects, provided herein is a binding agent (e.g.,anti-idiotype antibody and fragments thereof, such as Fab fragment)which specifically binds a target anti-FXI/FXIa antibody (e.g., NOV1401comprising a VH comprising the amino acid sequence of SEQ ID NO: 12 anda VL comprising the amino acid sequence of SEQ ID NO: 23), wherein thebinding agent inhibits an anticoagulant activity of the targetanti-FXI/FXIa antibody, wherein the binding agent is an antibody orantigen-binding fragment thereof comprising (1) a VH comprisingcomplementarity determining regions HCDR1, HCDR2, and HCDR3, and (2) aVL comprising complementarity determining regions LCDR1, LCDR2, andLCDR3; wherein the HCDR1 comprises the amino acid sequence of SEQ ID NO:286, the HCDR2 comprises the amino acid sequence of SEQ ID NO: 287, theHCDR3 comprises the amino acid sequence of SEQ ID NO: 288, the LCDR1comprises the amino acid sequence of SEQ ID NO: 302, the LCDR2 comprisesthe amino acid sequence of SEQ ID NO: 303, and the LCDR3 comprises theamino acid sequence of SEQ ID NO: 304.

In particular aspects, provided herein is a binding agent (e.g.,anti-idiotype antibody and fragments thereof, such as Fab fragment)which specifically binds a target anti-FXI/FXIa antibody (e.g., NOV1401comprising a VH comprising the amino acid sequence of SEQ ID NO: 12 anda VL comprising the amino acid sequence of SEQ ID NO: 23), wherein thebinding agent inhibits an anticoagulant activity of the targetanti-FXI/FXIa antibody, wherein the binding agent is an antibody orantigen-binding fragment thereof comprising (1) a VH comprisingcomplementarity determining regions HCDR1, HCDR2, and HCDR3, and (2) aVL comprising complementarity determining regions LCDR1, LCDR2, andLCDR3; wherein the HCDR1 comprises the amino acid sequence of SEQ ID NO:289, the HCDR2 comprises the amino acid sequence of SEQ ID NO: 290, theHCDR3 comprises the amino acid sequence of SEQ ID NO: 291, the LCDR1comprises the amino acid sequence of SEQ ID NO: 305, the LCDR2 comprisesthe amino acid sequence of SEQ ID NO: 306, and the LCDR3 comprises theamino acid sequence of SEQ ID NO: 307.

In particular aspects, provided herein is a binding agent (e.g.,anti-idiotype antibody and fragments thereof, such as Fab fragment)which specifically binds a target anti-FXI/FXIa antibody (e.g., NOV1401comprising a VH comprising the amino acid sequence of SEQ ID NO: 12 anda VL comprising the amino acid sequence of SEQ ID NO: 23), wherein thebinding agent inhibits an anticoagulant activity of the targetanti-FXI/FXIa antibody, wherein the binding agent is an antibody orantigen-binding fragment thereof comprising (1) a VH comprisingcomplementarity determining regions HCDR1, HCDR2, and HCDR3, and (2) aVL comprising complementarity determining regions LCDR1, LCDR2, andLCDR3; wherein the HCDR1 comprises the amino acid sequence of SEQ ID NO:292, the HCDR2 comprises the amino acid sequence of SEQ ID NO: 293, theHCDR3 comprises the amino acid sequence of SEQ ID NO: 294, the LCDR1comprises the amino acid sequence of SEQ ID NO: 308, the LCDR2 comprisesthe amino acid sequence of SEQ ID NO: 309, and the LCDR3 comprises theamino acid sequence of SEQ ID NO: 310.

In particular aspects, provided herein is a binding agent (e.g.,anti-idiotype antibody and fragments thereof, such as Fab fragment)which specifically binds a target anti-FXI/FXIa antibody (e.g., NOV1401comprising a VH comprising the amino acid sequence of SEQ ID NO: 12 anda VL comprising the amino acid sequence of SEQ ID NO: 23), wherein thebinding agent inhibits an anticoagulant activity of the targetanti-FXI/FXIa antibody, wherein the binding agent is an antibody orantigen-binding fragment thereof comprising (1) a VH comprisingcomplementarity determining regions HCDR1, HCDR2, and HCDR3, and (2) aVL comprising complementarity determining regions LCDR1, LCDR2, andLCDR3; wherein the HCDR1 comprises the amino acid sequence of SEQ ID NO:315, the HCDR2 comprises the amino acid sequence of SEQ ID NO: 316, theHCDR3 comprises the amino acid sequence of SEQ ID NO: 317, the LCDR1comprises the amino acid sequence of SEQ ID NO: 331, the LCDR2 comprisesthe amino acid sequence of SEQ ID NO: 332, and the LCDR3 comprises theamino acid sequence of SEQ ID NO: 333.

In particular aspects, provided herein is a binding agent (e.g.,anti-idiotype antibody and fragments thereof, such as Fab fragment)which specifically binds a target anti-FXI/FXIa antibody (e.g., NOV1401comprising a VH comprising the amino acid sequence of SEQ ID NO: 12 anda VL comprising the amino acid sequence of SEQ ID NO: 23), wherein thebinding agent inhibits an anticoagulant activity of the targetanti-FXI/FXIa antibody, wherein the binding agent is an antibody orantigen-binding fragment thereof comprising (1) a VH comprisingcomplementarity determining regions HCDR1, HCDR2, and HCDR3, and (2) aVL comprising complementarity determining regions LCDR1, LCDR2, andLCDR3; wherein the HCDR1 comprises the amino acid sequence of SEQ ID NO:318, the HCDR2 comprises the amino acid sequence of SEQ ID NO: 319, theHCDR3 comprises the amino acid sequence of SEQ ID NO: 320, the LCDR1comprises the amino acid sequence of SEQ ID NO: 334, the LCDR2 comprisesthe amino acid sequence of SEQ ID NO: 335, and the LCDR3 comprises theamino acid sequence of SEQ ID NO: 336.

In particular aspects, provided herein is a binding agent (e.g.,anti-idiotype antibody and fragments thereof, such as Fab fragment)which specifically binds a target anti-FXI/FXIa antibody (e.g., NOV1401comprising a VH comprising the amino acid sequence of SEQ ID NO: 12 anda VL comprising the amino acid sequence of SEQ ID NO: 23), wherein thebinding agent inhibits an anticoagulant activity of the targetanti-FXI/FXIa antibody, wherein the binding agent is an antibody orantigen-binding fragment thereof comprising (1) a VH comprisingcomplementarity determining regions HCDR1, HCDR2, and HCDR3, and (2) aVL comprising complementarity determining regions LCDR1, LCDR2, andLCDR3; wherein the HCDR1 comprises the amino acid sequence of SEQ ID NO:321, the HCDR2 comprises the amino acid sequence of SEQ ID NO: 322, theHCDR3 comprises the amino acid sequence of SEQ ID NO: 323, the LCDR1comprises the amino acid sequence of SEQ ID NO: 337, the LCDR2 comprisesthe amino acid sequence of SEQ ID NO: 338, and the LCDR3 comprises theamino acid sequence of SEQ ID NO: 339.

In particular aspects, provided herein is a binding agent (e.g.,anti-idiotype antibody and fragments thereof, such as Fab fragment)which specifically binds a target anti-FXI/FXIa antibody (e.g., NOV1401comprising a VH comprising the amino acid sequence of SEQ ID NO: 12 anda VL comprising the amino acid sequence of SEQ ID NO: 23), wherein thebinding agent inhibits an anticoagulant activity of the targetanti-FXI/FXIa antibody, wherein the binding agent is an antibody orantigen-binding fragment thereof comprising (1) a VH comprisingcomplementarity determining regions HCDR1, HCDR2, and HCDR3, and (2) aVL comprising complementarity determining regions LCDR1, LCDR2, andLCDR3; wherein the HCDR1 comprises the amino acid sequence of SEQ ID NO:324, the HCDR2 comprises the amino acid sequence of SEQ ID NO: 325, theHCDR3 comprises the amino acid sequence of SEQ ID NO: 326, the LCDR1comprises the amino acid sequence of SEQ ID NO: 340, the LCDR2 comprisesthe amino acid sequence of SEQ ID NO: 341, and the LCDR3 comprises theamino acid sequence of SEQ ID NO: 342.

Since each of the binding agents (e.g., antibodies) disclosed in Table2, can bind to anti-FXI/FXIa antibody NOV1401, the VH, VL, full lengthlight chain, and full length heavy chain sequences (amino acid sequencesand the nucleotide sequences encoding the amino acid sequences) can be“mixed and matched” to create other anti-FXI/FXIa antibody bindingagents. Such “mixed and matched” anti-FXI/FXIa antibody binding agentscan be tested using the binding assays known in the art (e.g., ELISAs,and other assays described in the Example section). When these chainsare mixed and matched, a VH sequence from a particular VH/VL pairingshould be replaced with a structurally similar VH sequence. Likewise afull length heavy chain sequence from a particular full length heavychain/full length light chain pairing should be replaced with astructurally similar full length heavy chain sequence. Likewise, a VLsequence from a particular VH/VL pairing should be replaced with astructurally similar VL sequence. Likewise a full length light chainsequence from a particular full length heavy chain/full length lightchain pairing should be replaced with a structurally similar full lengthlight chain sequence.

In particular aspects, provided herein is a binding agent (e.g.,anti-idiotype antibody and fragments thereof, such as Fab fragment)which specifically binds a target anti-FXI/FXIa antibody (e.g., NOV1401comprising a VH comprising the amino acid sequence of SEQ ID NO: 12 anda VL comprising the amino acid sequence of SEQ ID NO: 23), wherein thebinding agent inhibits an anticoagulant activity of the targetanti-FXI/FXIa antibody, wherein the binding agent is an antibody orantigen-binding fragment thereof comprising a VH and a VL, wherein theVH comprises the amino acid sequence of SEQ ID NO: 39, 71, 103, 135,167, 199, 231, 263, 295, or 327, and the VL comprises the amino acidsequence of SEQ ID NO: 55, 87, 119, 151, 183, 215, 247, 279, 311, or343.

In particular aspects, provided herein is a binding agent (e.g.,anti-idiotype antibody and fragments thereof, such as Fab fragment)which specifically binds a target anti-FXI/FXIa antibody (e.g., NOV1401comprising a VH comprising the amino acid sequence of SEQ ID NO: 12 anda VL comprising the amino acid sequence of SEQ ID NO: 23), wherein thebinding agent inhibits an anticoagulant activity of the targetanti-FXI/FXIa antibody, wherein the binding agent is an antibody orantigen-binding fragment thereof comprising a VH and a VL, wherein theVH comprises the amino acid sequence of SEQ ID NO: 39 and the VLcomprises the amino acid sequence of SEQ ID NO: 55.

In particular aspects, provided herein is a binding agent (e.g.,anti-idiotype antibody and fragments thereof, such as Fab fragment)which specifically binds a target anti-FXI/FXIa antibody (e.g., NOV1401comprising a VH comprising the amino acid sequence of SEQ ID NO: 12 anda VL comprising the amino acid sequence of SEQ ID NO: 23), wherein thebinding agent inhibits an anticoagulant activity of the targetanti-FXI/FXIa antibody, wherein the binding agent is an antibody orantigen-binding fragment thereof comprising a VH and a VL, and whereinthe VH comprises the amino acid sequence of SEQ ID NO: 71 and the VLcomprises the amino acid sequence of SEQ ID NO: 87.

In particular aspects, provided herein is a binding agent (e.g.,anti-idiotype antibody and fragments thereof, such as Fab fragment)which specifically binds a target anti-FXI/FXIa antibody (e.g., NOV1401comprising a VH comprising the amino acid sequence of SEQ ID NO: 12 anda VL comprising the amino acid sequence of SEQ ID NO: 23), wherein thebinding agent inhibits an anticoagulant activity of the targetanti-FXI/FXIa antibody, wherein the binding agent is an antibody orantigen-binding fragment thereof comprising a VH and a VL, and whereinthe VH comprises the amino acid sequence of SEQ ID NO: 103 and the VLcomprises the amino acid sequence of SEQ ID NO: 119.

In particular aspects, provided herein is a binding agent (e.g.,anti-idiotype antibody and fragments thereof, such as Fab fragment)which specifically binds a target anti-FXI/FXIa antibody (e.g., NOV1401comprising a VH comprising the amino acid sequence of SEQ ID NO: 12 anda VL comprising the amino acid sequence of SEQ ID NO: 23), wherein thebinding agent inhibits an anticoagulant activity of the targetanti-FXI/FXIa antibody, wherein the binding agent is an antibody orantigen-binding fragment thereof comprising a VH and a VL, and whereinthe VH comprises the amino acid sequence of SEQ ID NO: 135 and the VLcomprises the amino acid sequence of SEQ ID NO: 151.

In particular aspects, provided herein is a binding agent (e.g.,anti-idiotype antibody and fragments thereof, such as Fab fragment)which specifically binds a target anti-FXI/FXIa antibody (e.g., NOV1401comprising a VH comprising the amino acid sequence of SEQ ID NO: 12 anda VL comprising the amino acid sequence of SEQ ID NO: 23), wherein thebinding agent inhibits an anticoagulant activity of the targetanti-FXI/FXIa antibody, wherein the binding agent is an antibody orantigen-binding fragment thereof comprising a VH and a VL, and whereinthe VH comprises the amino acid sequence of SEQ ID NO: 167 and the VLcomprises the amino acid sequence of SEQ ID NO: 183.

In particular aspects, provided herein is a binding agent (e.g.,anti-idiotype antibody and fragments thereof, such as Fab fragment)which specifically binds a target anti-FXI/FXIa antibody (e.g., NOV1401comprising a VH comprising the amino acid sequence of SEQ ID NO: 12 anda VL comprising the amino acid sequence of SEQ ID NO: 23), wherein thebinding agent inhibits an anticoagulant activity of the targetanti-FXI/FXIa antibody, wherein the binding agent is an antibody orantigen-binding fragment thereof comprising a VH and a VL, and whereinthe VH comprises the amino acid sequence of SEQ ID NO: 199 and the VLcomprises the amino acid sequence of SEQ ID NO: 215.

In particular aspects, provided herein is a binding agent (e.g.,anti-idiotype antibody and fragments thereof, such as Fab fragment)which specifically binds a target anti-FXI/FXIa antibody (e.g., NOV1401comprising a VH comprising the amino acid sequence of SEQ ID NO: 12 anda VL comprising the amino acid sequence of SEQ ID NO: 23), wherein thebinding agent inhibits an anticoagulant activity of the targetanti-FXI/FXIa antibody, wherein the binding agent is an antibody orantigen-binding fragment thereof comprising a VH and a VL, and whereinthe VH comprises the amino acid sequence of SEQ ID NO: 231 and the VLcomprises the amino acid sequence of SEQ ID NO: 247.

In particular aspects, provided herein is a binding agent (e.g.,anti-idiotype antibody and fragments thereof, such as Fab fragment)which specifically binds a target anti-FXI/FXIa antibody (e.g., NOV1401comprising a VH comprising the amino acid sequence of SEQ ID NO: 12 anda VL comprising the amino acid sequence of SEQ ID NO: 23), wherein thebinding agent inhibits an anticoagulant activity of the targetanti-FXI/FXIa antibody, wherein the binding agent is an antibody orantigen-binding fragment thereof comprising a VH and a VL, and whereinthe VH comprises the amino acid sequence of SEQ ID NO: 263 and the VLcomprises the amino acid sequence of SEQ ID NO: 279.

In particular aspects, provided herein is a binding agent (e.g.,anti-idiotype antibody and fragments thereof, such as Fab fragment)which specifically binds a target anti-FXI/FXIa antibody (e.g., NOV1401comprising a VH comprising the amino acid sequence of SEQ ID NO: 12 anda VL comprising the amino acid sequence of SEQ ID NO: 23), wherein thebinding agent inhibits an anticoagulant activity of the targetanti-FXI/FXIa antibody, wherein the binding agent is an antibody orantigen-binding fragment thereof comprising a VH and a VL, and whereinthe VH comprises the amino acid sequence of SEQ ID NO: 295 and the VLcomprises the amino acid sequence of SEQ ID NO: 311.

In particular aspects, provided herein is a binding agent (e.g.,anti-idiotype antibody and fragments thereof, such as Fab fragment)which specifically binds a target anti-FXI/FXIa antibody (e.g., NOV1401comprising a VH comprising the amino acid sequence of SEQ ID NO: 12 anda VL comprising the amino acid sequence of SEQ ID NO: 23), wherein thebinding agent inhibits an anticoagulant activity of the targetanti-FXI/FXIa antibody, wherein the binding agent is an antibody orantigen-binding fragment thereof comprising a VH and a VL, and whereinthe VH comprises the amino acid sequence of SEQ ID NO: 327 and the VLcomprises the amino acid sequence of SEQ ID NO: 343.

In particular aspects, provided herein is a binding agent (e.g.,anti-idiotype antibody and fragments thereof, such as Fab fragment)which specifically binds a target anti-FXI/FXIa antibody (e.g., NOV1401comprising a VH comprising the amino acid sequence of SEQ ID NO: 12 anda VL comprising the amino acid sequence of SEQ ID NO: 23), wherein thebinding agent inhibits an anticoagulant activity of the targetanti-FXI/FXIa antibody, wherein the binding agent is an antibody orantigen-binding fragment thereof comprising a heavy chain and a lightchain, wherein the heavy chain comprises the amino acid sequence of SEQID NO: 41, 73, 105, 137, 169, 201, 233, 265, 297, or 329, and the lightchain comprises the amino acid sequence of SEQ ID NO: 57, 89, 121, 153,185, 217, 249, 281, 313, or 345.

In particular aspects, provided herein is a binding agent (e.g.,anti-idiotype antibody and fragments thereof, such as Fab fragment)which specifically binds a target anti-FXI/FXIa antibody (e.g., NOV1401comprising a VH comprising the amino acid sequence of SEQ ID NO: 12 anda VL comprising the amino acid sequence of SEQ ID NO: 23), wherein thebinding agent inhibits an anticoagulant activity of the targetanti-FXI/FXIa antibody, wherein the binding agent is an antibody orantigen-binding fragment thereof comprising a heavy chain and a lightchain, and wherein the heavy chain comprises the amino acid sequence ofSEQ ID NO: 41 and the light chain comprises the amino acid sequence ofSEQ ID NO: 57.

In particular aspects, provided herein is a binding agent (e.g.,anti-idiotype antibody and fragments thereof, such as Fab fragment)which specifically binds a target anti-FXI/FXIa antibody (e.g., NOV1401comprising a VH comprising the amino acid sequence of SEQ ID NO: 12 anda VL comprising the amino acid sequence of SEQ ID NO: 23), wherein thebinding agent inhibits an anticoagulant activity of the targetanti-FXI/FXIa antibody, wherein the binding agent is an antibody orantigen-binding fragment thereof comprising a heavy chain and a lightchain, and wherein the heavy chain comprises the amino acid sequence ofSEQ ID NO: 73 and the light chain comprises the amino acid sequence ofSEQ ID NO: 89.

In particular aspects, provided herein is a binding agent (e.g.,anti-idiotype antibody and fragments thereof, such as Fab fragment)which specifically binds a target anti-FXI/FXIa antibody (e.g., NOV1401comprising a VH comprising the amino acid sequence of SEQ ID NO: 12 anda VL comprising the amino acid sequence of SEQ ID NO: 23), wherein thebinding agent inhibits an anticoagulant activity of the targetanti-FXI/FXIa antibody, wherein the binding agent is an antibody orantigen-binding fragment thereof comprising a heavy chain and a lightchain, and wherein the heavy chain comprises the amino acid sequence ofSEQ ID NO: 105 and the light chain comprises the amino acid sequence ofSEQ ID NO: 121.

In particular aspects, provided herein is a binding agent (e.g.,anti-idiotype antibody and fragments thereof, such as Fab fragment)which specifically binds a target anti-FXI/FXIa antibody (e.g., NOV1401comprising a VH comprising the amino acid sequence of SEQ ID NO: 12 anda VL comprising the amino acid sequence of SEQ ID NO: 23), wherein thebinding agent inhibits an anticoagulant activity of the targetanti-FXI/FXIa antibody, wherein the binding agent is an antibody orantigen-binding fragment thereof comprising a heavy chain and a lightchain, and wherein the heavy chain comprises the amino acid sequence ofSEQ ID NO: 137 and the light chain comprises the amino acid sequence ofSEQ ID NO: 153.

In particular aspects, provided herein is a binding agent (e.g.,anti-idiotype antibody and fragments thereof, such as Fab fragment)which specifically binds a target anti-FXI/FXIa antibody (e.g., NOV1401comprising a VH comprising the amino acid sequence of SEQ ID NO: 12 anda VL comprising the amino acid sequence of SEQ ID NO: 23), wherein thebinding agent inhibits an anticoagulant activity of the targetanti-FXI/FXIa antibody, wherein the binding agent is an antibody orantigen-binding fragment thereof comprising a heavy chain and a lightchain, and wherein the heavy chain comprises the amino acid sequence ofSEQ ID NO: 169 and the light chain comprises the amino acid sequence ofSEQ ID NO: 185.

In particular aspects, provided herein is a binding agent (e.g.,anti-idiotype antibody and fragments thereof, such as Fab fragment)which specifically binds a target anti-FXI/FXIa antibody (e.g., NOV1401comprising a VH comprising the amino acid sequence of SEQ ID NO: 12 anda VL comprising the amino acid sequence of SEQ ID NO: 23), wherein thebinding agent inhibits an anticoagulant activity of the targetanti-FXI/FXIa antibody, wherein the binding agent is an antibody orantigen-binding fragment thereof comprising a heavy chain and a lightchain, and wherein the heavy chain comprises the amino acid sequence ofSEQ ID NO: 201 and the light chain comprises the amino acid sequence ofSEQ ID NO: 217.

In particular aspects, provided herein is a binding agent (e.g.,anti-idiotype antibody and fragments thereof, such as Fab fragment)which specifically binds a target anti-FXI/FXIa antibody (e.g., NOV1401comprising a VH comprising the amino acid sequence of SEQ ID NO: 12 anda VL comprising the amino acid sequence of SEQ ID NO: 23), wherein thebinding agent inhibits an anticoagulant activity of the targetanti-FXI/FXIa antibody, wherein the binding agent is an antibody orantigen-binding fragment thereof comprising a heavy chain and a lightchain, and wherein the heavy chain comprises the amino acid sequence ofSEQ ID NO: 233 and the light chain comprises the amino acid sequence ofSEQ ID NO: 249.

In particular aspects, provided herein is a binding agent (e.g.,anti-idiotype antibody and fragments thereof, such as Fab fragment)which specifically binds a target anti-FXI/FXIa antibody (e.g., NOV1401comprising a VH comprising the amino acid sequence of SEQ ID NO: 12 anda VL comprising the amino acid sequence of SEQ ID NO: 23), wherein thebinding agent inhibits an anticoagulant activity of the targetanti-FXI/FXIa antibody, wherein the binding agent is an antibody orantigen-binding fragment thereof comprising a heavy chain and a lightchain, and wherein the heavy chain comprises the amino acid sequence ofSEQ ID NO: 265 and the light chain comprises the amino acid sequence ofSEQ ID NO: 281.

In particular aspects, provided herein is a binding agent (e.g.,anti-idiotype antibody and fragments thereof, such as Fab fragment)which specifically binds a target anti-FXI/FXIa antibody (e.g., NOV1401comprising a VH comprising the amino acid sequence of SEQ ID NO: 12 anda VL comprising the amino acid sequence of SEQ ID NO: 23), wherein thebinding agent inhibits an anticoagulant activity of the targetanti-FXI/FXIa antibody, wherein the binding agent is an antibody orantigen-binding fragment thereof comprising a heavy chain and a lightchain, and wherein the heavy chain comprises the amino acid sequence ofSEQ ID NO: 297 and the light chain comprises the amino acid sequence ofSEQ ID NO: 313.

In particular aspects, provided herein is a binding agent (e.g.,anti-idiotype antibody and fragments thereof, such as Fab fragment)which specifically binds a target anti-FXI/FXIa antibody (e.g., NOV1401comprising a VH comprising the amino acid sequence of SEQ ID NO: 12 anda VL comprising the amino acid sequence of SEQ ID NO: 23), wherein thebinding agent inhibits an anticoagulant activity of the targetanti-FXI/FXIa antibody, wherein the binding agent is an antibody orantigen-binding fragment thereof comprising a heavy chain and a lightchain, and wherein the heavy chain comprises the amino acid sequence ofSEQ ID NO: 329 and the light chain comprises the amino acid sequence ofSEQ ID NO: 345.

In certain aspects, provided herein is a binding agent (e.g.,anti-idiotype antibody and fragments thereof, such as Fab fragment)which specifically binds a target anti-FXI/FXIa antibody, such asNOV1401 (e.g., comprising a VH comprising the amino acid sequence of SEQID NO: 12 and a VL comprising the amino acid sequence of SEQ ID NO: 23),wherein the binding agent inhibits an anticoagulant activity of thetarget anti-FXI/FXIa antibody, wherein the binding agent is an antibodyFab fragment of antibody IDT1, IDT2, IDT3, IDT4, IDT5, IDT6, IDT7, IDT8,IDT9, or IDT10, for example, as set forth in Table 2.

In certain aspects, provided herein is a binding agent (e.g.,anti-idiotype antibody and fragments thereof, such as Fab fragment)which specifically binds a target anti-FXI/FXIa antibody, such asNOV1401 (e.g., comprising a VH comprising the amino acid sequence of SEQID NO: 12 and a VL comprising the amino acid sequence of SEQ ID NO: 23),wherein the binding agent inhibits an anticoagulant activity of thetarget anti-FXI/FXIa antibody, wherein the binding agent is an antibodyFab fragment of antibody IDT1, IDT2, IDT3, IDT4, IDT5, IDT6, IDT7, IDT8,IDT9, or IDT10, for example, as set forth in Table 2, and is arecombinant, monoclonal human antibody.

As used herein, a human antibody comprises heavy or light chain variableregions or full length heavy or light chains that are “the product of”or “derived from” a particular germline sequence if the variable regionsor full length chains of the antibody are obtained from a system thatuses human germline immunoglobulin genes. Such systems includeimmunizing a transgenic mouse carrying human immunoglobulin genes withthe antigen of interest or screening a human immunoglobulin gene librarydisplayed on phage with the antigen of interest. A human antibody thatis “the product of” or “derived from” a human germline immunoglobulinsequence can be identified as such by comparing the amino acid sequenceof the human antibody to the amino acid sequences of human germlineimmunoglobulins and selecting the human germline immunoglobulin sequencethat is closest in sequence (i.e., greatest % identity) to the sequenceof the human antibody.

A human antibody that is “the product of” or “derived from” a particularhuman germline immunoglobulin sequence may contain amino aciddifferences as compared to the germline sequence, due to, for example,naturally occurring somatic mutations or intentional introduction ofsite-directed mutations. However, in specific aspects, in the VH or VLframework regions, a selected human antibody typically is at least 90%identical in amino acids sequence to an amino acid sequence encoded by ahuman germline immunoglobulin gene and contains amino acid residues thatidentify the human antibody as being human when compared to the germlineimmunoglobulin amino acid sequences of other species (e.g., murinegermline sequences). In certain cases, a human antibody may be at least60%, 70%, 80%, 90%, or at least 95%, or even at least 96%, 97%, 98%, or99% identical in amino acid sequence to the amino acid sequence encodedby the germline immunoglobulin gene.

In specific aspects, typically, a recombinant human antibody willdisplay no more than 10 amino acid differences from the amino acidsequence encoded by the human germline immunoglobulin gene in the VH orVL framework regions. In certain cases, the human antibody may displayno more than 5, or even no more than 4, 3, 2, or 1 amino acid differencefrom the amino acid sequence encoded by the germline immunoglobulingene. Examples of human germline immunoglobulin genes include, but arenot limited to the variable domain germline fragments described here, aswell as DP47 and DPK9.

Homologous Antibodies

In another aspect, the present disclosure provides a binding agentcomprising amino acid sequences that are homologous to sequencesdescribed in Table 2, wherein the binding agent binds to ananti-FXI/FXIa antibody, and retains the desired functional properties(e.g., reversal of one or more anticoagulant effects) of thoseantibodies described in Table 2 such as any one of antibodiesIDT1-IDT10. In specific aspects, such homologous antibodies retain theCDR amino acid sequences described in Table 2 (e.g., Kabat CDRs, ChothiaCDRs, IMGT CDRs, or Combined CDRs).

In particular aspects, provided herein is a binding agent (e.g.,anti-idiotype antibody and fragments thereof, such as Fab fragment)which specifically binds a target anti-FXI/FXIa antibody (e.g., NOV1401comprising a VH comprising the amino acid sequence of SEQ ID NO: 12 anda VL comprising the amino acid sequence of SEQ ID NO: 23), wherein thebinding agent inhibits an anticoagulant activity of the targetanti-FXI/FXIa antibody, wherein the binding agent is an antibody orantigen-binding fragment thereof comprising a VH and a VL, and whereinthe VH and VL comprise amino acid sequences that are at least 80%, atleast 85%, at least 90%, at least 91%, at least 92%, at least 93%, atleast 94%, at least 95%, at least 96%, at least 97%, at least 98% or atleast 99% identical to the VH and VL sequences selected from Table 2. Ina further specific aspect, the differences in amino acid sequence in theVL and/or VH of the binding agent is not within the complementaritydetermining regions.

In particular aspects, provided herein is a binding agent (e.g.,anti-idiotype antibody and fragments thereof, such as Fab fragment)which specifically binds a target anti-FXI/FXIa antibody (e.g., NOV1401comprising a VH comprising the amino acid sequence of SEQ ID NO: 12 anda VL comprising the amino acid sequence of SEQ ID NO: 23), wherein thebinding agent inhibits an anticoagulant activity of the targetanti-FXI/FXIa antibody, wherein the binding agent is an antibody orantigen-binding fragment thereof comprising a VH and a VL, and whereinthe VH comprises an amino acid sequence that is at least 90% or at least95% identical to the amino acid sequence of SEQ ID NO: 39 and the VLcomprises an amino acid sequence that is at least 90% or at least 95%identical to the amino acid sequence of SEQ ID NO: 55. In a furtherspecific aspect, the differences in amino acid sequence in the VL and/orVH of the binding agent is not within the complementarity determiningregions.

In particular aspects, provided herein is a binding agent (e.g.,anti-idiotype antibody and fragments thereof, such as Fab fragment)which specifically binds a target anti-FXI/FXIa antibody (e.g., NOV1401comprising a VH comprising the amino acid sequence of SEQ ID NO: 12 anda VL comprising the amino acid sequence of SEQ ID NO: 23), wherein thebinding agent inhibits an anticoagulant activity of the targetanti-FXI/FXIa antibody, wherein the binding agent is an antibody orantigen-binding fragment thereof comprising a VH and a VL, and whereinthe VH comprises an amino acid sequence that is at least 90% or at least95% identical to the amino acid sequence of SEQ ID NO: 71 and the VLcomprises the amino acid sequence of SEQ ID NO: 87. In a furtherspecific aspect, the differences in amino acid sequence in the VL and/orVH of the binding agent is not within the complementarity determiningregions.

In particular aspects, provided herein is a binding agent (e.g.,anti-idiotype antibody and fragments thereof, such as Fab fragment)which specifically binds a target anti-FXI/FXIa antibody (e.g., NOV1401comprising a VH comprising the amino acid sequence of SEQ ID NO: 12 anda VL comprising the amino acid sequence of SEQ ID NO: 23), wherein thebinding agent inhibits an anticoagulant activity of the targetanti-FXI/FXIa antibody, wherein the binding agent is an antibody orantigen-binding fragment thereof comprising a VH and a VL, and whereinthe VH comprises an amino acid sequence that is at least 90% or at least95% identical to the amino acid sequence of SEQ ID NO: 103 and the VLcomprises the amino acid sequence of SEQ ID NO: 119. In a furtherspecific aspect, the differences in amino acid sequence in the VL and/orVH of the binding agent is not within the complementarity determiningregions.

In particular aspects, provided herein is a binding agent (e.g.,anti-idiotype antibody and fragments thereof, such as Fab fragment)which specifically binds a target anti-FXI/FXIa antibody (e.g., NOV1401comprising a VH comprising the amino acid sequence of SEQ ID NO: 12 anda VL comprising the amino acid sequence of SEQ ID NO: 23), wherein thebinding agent inhibits an anticoagulant activity of the targetanti-FXI/FXIa antibody, wherein the binding agent is an antibody orantigen-binding fragment thereof comprising a VH and a VL, and whereinthe VH comprises an amino acid sequence that is at least 90% or at least95% identical to the amino acid sequence of SEQ ID NO: 135 and the VLcomprises an amino acid sequence that is at least 90% or at least 95%identical to the amino acid sequence of SEQ ID NO: 151. In a furtherspecific aspect, the differences in amino acid sequence in the VL and/orVH of the binding agent is not within the complementarity determiningregions.

In particular aspects, provided herein is a binding agent (e.g.,anti-idiotype antibody and fragments thereof, such as Fab fragment)which specifically binds a target anti-FXI/FXIa antibody (e.g., NOV1401comprising a VH comprising the amino acid sequence of SEQ ID NO: 12 anda VL comprising the amino acid sequence of SEQ ID NO: 23), wherein thebinding agent inhibits an anticoagulant activity of the targetanti-FXI/FXIa antibody, wherein the binding agent is an antibody orantigen-binding fragment thereof comprising a VH and a VL, and whereinthe VH comprises an amino acid sequence that is at least 90% or at least95% identical to the amino acid sequence of SEQ ID NO: 167 and the VLcomprises an amino acid sequence that is at least 90% or at least 95%identical to the amino acid sequence of SEQ ID NO: 183. In a furtherspecific aspect, the differences in amino acid sequence in the VL and/orVH of the binding agent is not within the complementarity determiningregions.

In particular aspects, provided herein is a binding agent (e.g.,anti-idiotype antibody and fragments thereof, such as Fab fragment)which specifically binds a target anti-FXI/FXIa antibody (e.g., NOV1401comprising a VH comprising the amino acid sequence of SEQ ID NO: 12 anda VL comprising the amino acid sequence of SEQ ID NO: 23), wherein thebinding agent inhibits an anticoagulant activity of the targetanti-FXI/FXIa antibody, wherein the binding agent is an antibody orantigen-binding fragment thereof comprising a VH and a VL, and whereinthe VH comprises an amino acid sequence that is at least 90% or at least95% identical to the amino acid sequence of SEQ ID NO: 199 and the VLcomprises an amino acid sequence that is at least 90% or at least 95%identical to the amino acid sequence of SEQ ID NO: 215. In a furtherspecific aspect, the differences in amino acid sequence in the VL and/orVH of the binding agent is not within the complementarity determiningregions.

In particular aspects, provided herein is a binding agent (e.g.,anti-idiotype antibody and fragments thereof, such as Fab fragment)which specifically binds a target anti-FXI/FXIa antibody (e.g., NOV1401comprising a VH comprising the amino acid sequence of SEQ ID NO: 12 anda VL comprising the amino acid sequence of SEQ ID NO: 23), wherein thebinding agent inhibits an anticoagulant activity of the targetanti-FXI/FXIa antibody, wherein the binding agent is an antibody orantigen-binding fragment thereof comprising a VH and a VL, and whereinthe VH comprises an amino acid sequence that is at least 90% or at least95% identical to the amino acid sequence of SEQ ID NO: 231 and the VLcomprises an amino acid sequence that is at least 90% or at least 95%identical to the amino acid sequence of SEQ ID NO: 247. In a furtherspecific aspect, the differences in amino acid sequence in the VL and/orVH of the binding agent is not within the complementarity determiningregions.

In particular aspects, provided herein is a binding agent (e.g.,anti-idiotype antibody and fragments thereof, such as Fab fragment)which specifically binds a target anti-FXI/FXIa antibody (e.g., NOV1401comprising a VH comprising the amino acid sequence of SEQ ID NO: 12 anda VL comprising the amino acid sequence of SEQ ID NO: 23), wherein thebinding agent inhibits an anticoagulant activity of the targetanti-FXI/FXIa antibody, wherein the binding agent is an antibody orantigen-binding fragment thereof comprising a VH and a VL, and whereinthe VH comprises an amino acid sequence that is at least 90% or at least95% identical to the amino acid sequence of SEQ ID NO: 263 and the VLcomprises an amino acid sequence that is at least 90% or at least 95%identical to the amino acid sequence of SEQ ID NO: 279. In a furtherspecific aspect, the differences in amino acid sequence in the VL and/orVH of the binding agent is not within the complementarity determiningregions.

In particular aspects, provided herein is a binding agent (e.g.,anti-idiotype antibody and fragments thereof, such as Fab fragment)which specifically binds a target anti-FXI/FXIa antibody (e.g., NOV1401comprising a VH comprising the amino acid sequence of SEQ ID NO: 12 anda VL comprising the amino acid sequence of SEQ ID NO: 23), wherein thebinding agent inhibits an anticoagulant activity of the targetanti-FXI/FXIa antibody, wherein the binding agent is an antibody orantigen-binding fragment thereof comprising a VH and a VL, and whereinthe VH comprises an amino acid sequence that is at least 90% or at least95% identical to the amino acid sequence of SEQ ID NO: 295 and the VLcomprises an amino acid sequence that is at least 90% or at least 95%identical to the amino acid sequence of SEQ ID NO: 311. In a furtherspecific aspect, the differences in amino acid sequence in the VL and/orVH of the binding agent is not within the complementarity determiningregions.

In particular aspects, provided herein is a binding agent (e.g.,anti-idiotype antibody and fragments thereof, such as Fab fragment)which specifically binds a target anti-FXI/FXIa antibody (e.g., NOV1401comprising a VH comprising the amino acid sequence of SEQ ID NO: 12 anda VL comprising the amino acid sequence of SEQ ID NO: 23), wherein thebinding agent inhibits an anticoagulant activity of the targetanti-FXI/FXIa antibody, wherein the binding agent is an antibody orantigen-binding fragment thereof comprising a VH and a VL, and whereinthe VH comprises an amino acid sequence that is at least 90% or at least95% identical to the amino acid sequence of SEQ ID NO: 327 and the VLcomprises an amino acid sequence that is at least 90% or at least 95%identical to the amino acid sequence of SEQ ID NO: 343. In a furtherspecific aspect, the differences in amino acid sequence in the VL and/orVH of the binding agent is not within the complementarity determiningregions.

As used herein, the percent identity between the two sequences is afunction of the number of identical positions shared by the sequences(i.e., % identity equals number of identical positions/total number ofpositions×100), taking into account the number of gaps, and the lengthof each gap, which need to be introduced for optimal alignment of thetwo sequences. The comparison of sequences and determination of percentidentity between two sequences can be accomplished using a mathematicalalgorithm, as described in the non-limiting examples below.

Additionally or alternatively, the protein sequences of the presentinvention can further be used as a “query sequence” to perform a searchagainst public databases to, for example, identify related sequences.For example, such searches can be performed using the BLAST program(version 2.0) of Altschul, et al., 1990 J. Mol. Biol. 215:403-10.

The present disclosure also provides a binding agent (e.g.,anti-idiotype antibody and fragments thereof, such as Fab fragment)which specifically binds a target anti-FXI/FXIa antibody (e.g.,NOV1401), wherein the binding agent is an antibody or antigen-bindingfragment thereof comprising (or alternatively, consisting of) a VH aminoacid sequence listed in Table 2, wherein no more than about 1, 2, 3, 4,5, 6, 7, 8, 9,10, 11, 12, 13, 14, 15, 16, 17, 18, 19, or 20 amino acidsin a framework sequence (for example, a sequence which is not a CDR)have been mutated (wherein a mutation is, as various non-limitingexamples, an addition, substitution or deletion).

The present disclosure also provides a binding agent (e.g.,anti-idiotype antibody and fragments thereof, such as Fab fragment)which specifically binds a target anti-FXI/FXIa antibody (e.g.,NOV1401), wherein the binding agent is an antibody or antigen-bindingfragment thereof comprising (or alternatively, consisting of) a VL aminoacid sequence listed in Table 2, wherein no more than about 1, 2, 3, 4,5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, or 20 amino acidsin a framework sequence (for example, a sequence which is not a CDR)have been mutated (wherein a mutation is, as various non-limitingexamples, an addition, substitution or deletion).

Antibodies with Conservative Modifications

In certain aspects, the present disclosure relates to a binding agent,which is an antibody or antigen-binding fragment thereof (e.g., Fabfragment) that specifically binds to an anti-FXI/FXIa antibody such asNOV1401, wherein the binding agent comprises VH comprising CDR1, CDR2,and CDR3 sequences and a VL comprising CDR1, CDR2, and CDR3 sequences,wherein one or more of these CDR sequences have specified amino acidsequences based on the antibodies described herein, such as thosedescribed in Table 2, or conservative modifications thereof, and whereinthe binding agents retain the desired functional properties (e.g.,reversing one or more anticoagulant effects of an anti-FXI/FXIaantibody) of the binding agents described herein, e.g., binding agentsIDT1, IDT2, IDT3, IDT4, IDT5, IDT6, IDT7, IDT8, IDT9, or IDT10.

In specific aspects, a binding agent described herein, which is anantibody or antigen-binding fragment thereof (e.g., Fab fragment) thatspecifically binds to an anti-FXI/FXIa antibody such as NOV1401,comprises VH comprising CDR1, CDR2, and CDR3 sequences and a VLcomprising CDR1, CDR2, and CDR3 sequences set forth in Table 2 with one,two, three, or more conservative modifications in one or more CDRs, andwherein the binding agents retain the desired functional properties(e.g., binding to anti-FXI/FXIa antibody and/or reversing one or moreanticoagulant effects of an anti-FXI/FXIa antibody) of the bindingagents described herein, e.g., binding agents IDT1, IDT2, IDT3, IDT4,IDT5, IDT6, IDT7, IDT8, IDT9, or IDT10.

In further specific aspects, provided herein is a binding agent (e.g.,anti-idiotype antibody) which specifically binds a target anti-FXI/FXIaantibody such as NOV1401, wherein the binding agent inhibits ananticoagulant activity of the target anti-FXI/FXIa antibody, wherein thebinding agent is an antibody or antigen-binding fragment thereofcomprising (1) a VH comprising complementarity determining regionsHCDR1, HCDR2, and HCDR3 selected from those set forth in Table 2 andconservative modifications thereof, and (2) a VL comprisingcomplementarity determining regions LCDR1, LCDR2, and LCDR3 selectedfrom those set forth in Table 2 and conservative modifications thereof.In a particular aspect, the binding agent (e.g., anti-idiotype antibody)comprises Combined HCDR1, HCDR2, and HCDR3 selected from those set forthin Table 2 and conservative modifications thereof, and Combined LCDR1,LCDR2, and LCDR3 selected from those set forth in Table 2 andconservative modifications thereof. In a particular aspect, the bindingagent (e.g., anti-idiotype antibody) comprises Kabat HCDR1, HCDR2, andHCDR3 selected from those set forth in Table 2 and conservativemodifications thereof, and Kabat LCDR1, LCDR2, and LCDR3 selected fromthose set forth in Table 2 and conservative modifications thereof. In aparticular aspect, the binding agent (e.g., anti-idiotype antibody)comprises Chothia HCDR1, HCDR2, and HCDR3 selected from those set forthin Table 2 and conservative modifications thereof, and Chothia LCDR1,LCDR2, and LCDR3 selected from those set forth in Table 2 andconservative modifications thereof In a particular aspect, the bindingagent (e.g., anti-idiotype antibody) comprises IMGT HCDR1, HCDR2, andHCDR3 selected from those set forth in Table 2 and conservativemodifications thereof, and IMGT LCDR1, LCDR2, and LCDR3 selected fromthose set forth in Table 2 and conservative modifications thereof.

In particular aspects, provided herein is a binding agent (e.g.,anti-idiotype antibody and fragments thereof, such as Fab fragment)which specifically binds a target anti-FXI/FXIa antibody such asNOV1401, wherein the binding agent inhibits an anticoagulant activity ofthe target anti-FXI/FXIa antibody, wherein the binding agent is anantibody or antigen-binding fragment thereof comprising (1) a VHcomprising complementarity determining regions HCDR1, HCDR2, and HCDR3,and (2) a VL comprising complementarity determining regions LCDR1,LCDR2, and LCDR3; wherein:

-   -   a. the HCDR1 comprises the amino acid sequence of SEQ ID NO: 27,        59, 91, 123, 155, 187, 219, 251, 283, or 315, or conservative        modifications thereof;    -   b. the HCDR2 comprises the amino acid sequence of SEQ ID NO: 28,        60, 92, 124, 156, 188, 220, 252, 284, or 316, or conservative        modifications thereof;    -   c. the HCDR3 comprises the amino acid sequence of SEQ ID NO: 29,        61, 93, 125, 157, 189, 221, 253, 285, or 317, or conservative        modifications thereof;    -   d. the LCDR1 comprises the amino acid sequence of SEQ ID NO: 43,        75, 107, 139, 171, 203, 235, 267, 299, or 331, or conservative        modifications thereof;    -   e. the LCDR2 comprises the amino acid sequence of SEQ ID NO: 44,        76, 108, 140, 172, 204, 236, 268, 300, or 332, or conservative        modifications thereof; and    -   f. the LCDR3 comprises the amino acid sequence of SEQ ID NO: 45,        77, 109, 141, 173, 205, 237, 269, 301, or 333, or conservative        modifications thereof

In particular aspects, provided herein is a binding agent (e.g.,anti-idiotype antibody and fragments thereof, such as Fab fragment)which specifically binds a target anti-FXI/FXIa antibody such asNOV1401, wherein the binding agent inhibits an anticoagulant activity ofthe target anti-FXI/FXIa antibody, wherein the binding agent is anantibody or antigen-binding fragment thereof comprising (1) a VHcomprising complementarity determining regions HCDR1, HCDR2, and HCDR3,and (2) a VL comprising complementarity determining regions LCDR1,LCDR2, and LCDR3; wherein:

a. the HCDR1 comprises the amino acid sequence of SEQ ID NO: 30, 62, 94,126, 158, 190, 222, 254, 286, or 318, or conservative modificationsthereof;

-   -   b. the HCDR2 comprises the amino acid sequence of SEQ ID NO: 31,        63, 95, 127, 159, 191, 223, 255, 287, or 319, or conservative        modifications thereof;    -   c. the HCDR3 comprises the amino acid sequence of SEQ ID NO: 32,        64, 96, 128, 160, 192, 224, 256, 288, or 320, or conservative        modifications thereof;    -   d. the LCDR1 comprises the amino acid sequence of SEQ ID NO: 46,        78, 110, 142, 174, 206, 238, 270, 302, or 334, or conservative        modifications thereof;    -   e. the LCDR2 comprises the amino acid sequence of SEQ ID NO: 47,        79, 111, 143, 175, 207, 239, 271, 303, or 335, or conservative        modifications thereof; and    -   f. the LCDR3 comprises the amino acid sequence of SEQ ID NO: 48,        80, 112, 144, 176, 208, 240, 272, 304, or 336, or conservative        modifications thereof

The present disclosure also provides a binding agent (e.g.,anti-idiotype antibody and fragments thereof, such as Fab fragment)which specifically binds a target anti-FXI/FXIa antibody (e.g.,NOV1401), wherein the binding agent is an antibody or antigen-bindingfragment thereof comprising (or alternatively, consisting of) a VH aminoacid sequence listed in Table 2, wherein no more than about 1, 2, 3, 4,5, 6, 7, 8, 9,10, 11, 12, 13, 14, 15, 16, 17, 18, 19, or 20 amino acidsin a framework sequence (for example, a sequence which is not a CDR)have conservative modifications.

The present disclosure also provides a binding agent (e.g.,anti-idiotype antibody and fragments thereof, such as Fab fragment)which specifically binds a target anti-FXI/FXIa antibody (e.g.,NOV1401), wherein the binding agent is an antibody or antigen-bindingfragment thereof comprising (or alternatively, consisting of) a VL aminoacid sequence listed in Table 2, wherein no more than about 1, 2, 3, 4,5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, or 20 amino acidsin a framework sequence (for example, a sequence which is not a CDR)have conservative modifications.

Binding Agents that Bind to the Same Epitope

The present disclosure provides binding agents that bind to the sameepitope of an anti-FXI/FXIa antibody, such as NOV1401, as one of thebinding agents (e.g., antibodies) described in Table 2 (e.g., any one ofIDT1, IDT2, IDT3, IDT4, IDT5, IDT6, IDT7, IDT8, IDT9, and IDT10).Additional binding agents can therefore be identified based on theirability to compete (e.g., to competitively inhibit the binding of, in astatistically significant manner, by binding to the same or overlappingepitope) with other binding agents described herein in anti-FXI/FXIabinding assays (such as those described in the Examples Section).

The ability of a test binding agent to inhibit the binding of referencebinding agent described herein, such as antibody IDT3, to ananti-FXI/FXIa antibody such as NOV1401 demonstrates that the testbinding agent can compete with that reference binding agent for bindingto an anti-FXI/FXIa antibody such as NOV1401; such binding agent may,according to non-limiting theory, bind to the same or a related (e.g., astructurally similar or spatially proximal) epitope on the anti-FXI/FXIaantibody such as NOV1401 as the reference binding agent with which itcompetes. In a certain embodiment, the binding agent that binds to thesame epitope on an anti-FXI/FXIa antibody, such as NOV1401, as a bindingagent provided herein (e.g., antibody IDT3) is a human monoclonalantibody. Such human monoclonal antibodies can be prepared and isolatedas described herein.

As used herein, a binding agent (e.g., antibody) “competes” for bindingwhen the competing binding agent (e.g., antibody) binds to the sameanti-FXI/FXIa antibody epitope as a reference binding agent (e.g., anyone of antibodies IDT1-IDT10) and inhibits anti-FXI/FXIa antibodybinding of the reference binding agent by more than 40% or 50% (forexample, 60%, 70%, 80%, 85%, 90%, 95%, 98% or 99%) in the presence of anequimolar concentration of competing binding agent. This may bedetermined, for instance, in a competitive binding assay, by any of themethods well known to those of skill in the art.

As used herein, a binding agent (e.g., antibody or antigen bindingfragment thereof) does not “compete” with a reference binding agentprovided herein (e.g., anyone of antibody IDT1-IDT10) unless saidcompeting binding agent (e.g., antibody or antigen binding fragmentthereof) binds the same epitope, or an overlapping epitope, within ananti-FXI/FXIa antibody, such as NOV1401, as a reference binding agentprovided herein (e.g., any one of antibodies IDT1-IDT10). As usedherein, a competing binding agent (e.g., antibody or antigen bindingfragment thereof) does not include one which (i) sterically blocks areference binding agent provided herein (e.g., any one of antibodiesIDT1-IDT10) from binding its target (e.g., if said competing bindingagent binds to a nearby, non-overlapping epitope and physically preventsa reference binding agent provided herein from binding its target);and/or (ii) binds to a different, non-overlapping epitope within theanti-FXI/FXIa antibody and induces a conformational change to theanti-FXI/FXIa antibody such that said anti-FXI/FXIa antibody can nolonger be bound by a reference binding agent provided herein in a waythat would occur absent said conformational change.

Engineered and Modified Antibodies

Binding agents (e.g., anti-FXI/FXIa antibody binding agent) providedherein which are antibodies can be prepared using an antibody having oneor more of the VH and/or VL sequences shown herein as starting materialto engineer a modified antibody, which modified antibody may havealtered properties from the starting antibody. An antibody can beengineered by modifying one or more residues within one or both variableregions (i. e., VH and/or VL), for example within one or more CDRregions and/or within one or more framework regions. Additionally oralternatively, an antibody can be engineered by modifying residueswithin the constant region(s), for example to alter the effectorfunction(s) of the antibody.

One type of variable region engineering that can be performed is CDRgrafting. Antibodies interact with target antigens predominantly throughamino acid residues that are located in the six heavy and light chaincomplementarity determining regions (CDRs). For this reason, the aminoacid sequences within CDRs are more diverse between individualantibodies than sequences outside of CDRs. Because CDR sequences areresponsible for most antibody-antigen interactions, it is possible toexpress recombinant antibodies that mimic the properties of specificnaturally occurring antibodies by constructing expression vectors thatinclude CDR sequences from the specific naturally occurring antibodygrafted onto framework sequences from a different antibody withdifferent properties (see, e.g., Riechmann, L. et al., 1998 Nature332:323-327; Jones, P. et al., 1986 Nature 321:522-525; Queen, C. etal., 1989 Proc. Natl. Acad., U.S.A. 86:10029-10033; U.S. Pat. No.5,225,539 to Winter, and U.S. Pat. Nos. 5,530,101; 5,585,089; 5,693,762and 6,180,370 to Queen et al.)

Framework sequences can be obtained from public DNA databases orpublished references that include germline antibody gene sequences. Forexample, germline DNA sequences for human heavy and light chain variableregion genes can be found in the “VBase” human germline sequencedatabase (available on the world wide web at mrc-cpe.cam.ac.uk/vbase),as well as in Kabat, E. A., et al., 1991 Sequences of Proteins ofImmunological Interest, Fifth Edition, U.S. Department of Health andHuman Services, NIH Publication No. 91-3242; Tomlinson, I. M., et al.,1992 J. Mol. Biol. 227:776-798; and Cox, J. P. L. et al., 1994 Eur. JImmunol. 24:827-836; the contents of each of which are expresslyincorporated herein by reference.

An example of framework sequences for use in antibodies of the presentdisclosure are those that are structurally similar to the frameworksequences used by selected antibodies described herein, e.g., consensussequences and/or framework sequences used by monoclonal antibodies ofthe invention. The VH CDR1, 2 and 3 sequences, and the VL CDR1, 2 and 3sequences, can be grafted onto framework regions that have the identicalsequence as that found in the germline immunoglobulin gene from whichthe framework sequence derive, or the CDR sequences can be grafted ontoframework regions that contain one or more mutations as compared to thegermline sequences. For example, it has been found that in certaininstances it is beneficial to mutate residues within the frameworkregions to maintain or enhance the antigen binding ability of theantibody (see e.g., U.S. Pat. Nos. 5,530,101; 5,585,089; 5,693,762 and6,180,370 to Queen et al). Frameworks that can be utilized as scaffoldson which to build the antibodies and antigen binding fragments describedherein include, but are not limited to VH1A, VH1B, VH3, Vk1, V12, andVk2. Additional frameworks are known in the art and may be found, forexample, in the vBase data base on the world wide web atvbase.mrc-cpe.cam.ac.uk/index.php?&MMN_position=1:1.

Accordingly, in specific aspects, the present disclosure relates tobinding agents, such as isolated antibodies which bind an anti-FXI/FXIaantibody such as NOV1401, comprising a heavy chain variable regioncomprising an amino acid sequence selected from the group consisting ofSEQ ID NOs: 39, 71, 103, 135, 167, 199, 231, 263, 295, and 327, or anamino acid sequence having one, two, three, four or five amino acidsubstitutions, deletions or additions in the framework region of suchsequences, and further comprising a light chain variable regioncomprising an amino acid sequence selected from the group consisting ofSEQ ID NOs: 55, 87, 119, 151, 183, 215, 247, 279, 311, and 343, or anamino acid sequence having one, two, three, four or five amino acidsubstitutions, deletions or additions in the framework region of suchsequences.

Another type of variable region modification is to mutate amino acidresidues within the VH and/or VL CDR1, CDR2 and/or CDR3 regions tothereby improve one or more binding properties (e.g., affinity) of theantibody of interest, known as “affinity maturation.” Site-directedmutagenesis or PCR-mediated mutagenesis can be performed to introducethe mutation(s) and the effect on antibody binding, or other functionalproperty of interest, can be evaluated in in vitro or in vivo assays asdescribed herein and provided in the Examples Section. Conservativemodifications (as discussed above) can be introduced. The mutations maybe amino acid substitutions, additions or deletions. Moreover, typicallyno more than one, two, three, four or five residues within a CDR regionare altered.

Accordingly, in specific aspects, provided herein are affinity maturedvariants of antibody IDT1, IDT2, IDT3, IDT4, IDT5, IDT6, IDT7, IDT8,IDT9, or IDT10, wherein the affinity matured variant has higher affinityfor the anti-FXI/FXIa antibody NOV1401 than the parental, and is capableof reversing one or more anticoagulant effects of NOV1401. In particularaspects, provided herein is In particular aspects, provided herein is abinding agent (e.g., anti-idiotype antibody and fragments thereof, suchas Fab fragment) which specifically binds a target anti-FXI/FXIaantibody, wherein the binding agent inhibits an anticoagulant activityof the target anti-FXI/FXIa antibody, wherein the target anti-FXI/FXIaantibody is antibody NOV1401(comprising a VH comprising the amino acidsequence of SEQ ID NO: 12 and a VL comprising the amino acid sequence ofSEQ ID NO: 23), and wherein the binding agent is an antibody orantigen-binding fragment thereof comprising (1) a VH comprisingcomplementarity determining regions HCDR1, HCDR2, and HCDR3, and (2) aVL comprising complementarity determining regions LCDR1, LCDR2, andLCDR3; wherein:

-   -   a. the HCDR1 comprises the amino acid sequence of SEQ ID NO: 27,        59, 91, 123, 155, 187, 219, 251, 283, or 315, or an amino acid        sequence thereof having one, two, three, four or five amino acid        substitutions, deletions or additions;    -   b. the HCDR2 comprises the amino acid sequence of SEQ ID NO: 28,        60, 92, 124, 156, 188, 220, 252, 284, or 316, or an amino acid        sequence thereof having one, two, three, four or five amino acid        substitutions, deletions or additions;    -   c. the HCDR3 comprises the amino acid sequence of SEQ ID NO: 29,        61, 93, 125, 157, 189, 221, 253, 285, or 317, or an amino acid        sequence thereof having one, two, three, four or five amino acid        substitutions, deletions or additions;    -   d. the LCDR1 comprises the amino acid sequence of SEQ ID NO: 43,        75, 107, 139, 171, 203, 235, 267, 299, or 331, or an amino acid        sequence thereof having one, two, three, four or five amino acid        substitutions, deletions or additions;    -   e. the LCDR2 comprises the amino acid sequence of SEQ ID NO: 44,        76, 108, 140, 172, 204, 236, 268, 300, or 332, or an amino acid        sequence thereof having one, two, three, four or five amino acid        substitutions, deletions or additions; and    -   f. the LCDR3 comprises the amino acid sequence of SEQ ID NO: 45,        77, 109, 141, 173, 205, 237, 269, 301, or 333, or an amino acid        sequence thereof having one, two, three, four or five amino acid        substitutions, deletions or additions.

In particular aspects, provided herein is a binding agent (e.g.,anti-idiotype antibody and fragments thereof, such as Fab fragment)which specifically binds a target anti-FXI/FXIa antibody, wherein thebinding agent inhibits an anticoagulant activity of the targetanti-FXI/FXIa antibody, wherein the target anti-FXI/FXIa antibody isantibody NOV1401(comprising a VH comprising the amino acid sequence ofSEQ ID NO: 12 and a VL comprising the amino acid sequence of SEQ ID NO:23), and wherein the binding agent is an antibody or antigen-bindingfragment thereof comprising (1) a VH comprising complementaritydetermining regions HCDR1, HCDR2, and HCDR3, and (2) a VL comprisingcomplementarity determining regions LCDR1, LCDR2, and LCDR3; wherein:

-   -   a. the HCDR1 comprises the amino acid sequence of SEQ ID NO: 30,        62, 94, 126, 158, 190, 222, 254, 286, or 318, or an amino acid        sequence thereof having one, two, three, four or five amino acid        substitutions, deletions or additions;    -   b. the HCDR2 comprises the amino acid sequence of SEQ ID NO: 31,        63, 95, 127, 159, 191, 223, 255, 287, or 319, or an amino acid        sequence thereof having one, two, three, four or five amino acid        substitutions, deletions or additions;    -   c. the HCDR3 comprises the amino acid sequence of SEQ ID NO: 32,        64, 96, 128, 160, 192, 224, 256, 288, or 320, or an amino acid        sequence thereof having one, two, three, four or five amino acid        substitutions, deletions or additions;    -   d. the LCDR1 comprises the amino acid sequence of SEQ ID NO: 46,        78, 110, 142, 174, 206, 238, 270, 302, or 334, or an amino acid        sequence thereof having one, two, three, four or five amino acid        substitutions, deletions or additions;    -   e. the LCDR2 comprises the amino acid sequence of SEQ ID NO: 47,        79, 111, 143, 175, 207, 239, 271, 303, or 335, or an amino acid        sequence thereof having one, two, three, four or five amino acid        substitutions, deletions or additions; and    -   f. the LCDR3 comprises the amino acid sequence of SEQ ID NO: 48,        80, 112, 144, 176, 208, 240, 272, 304, or 336, or an amino acid        sequence thereof having one, two, three, four or five amino acid        substitutions, deletions or additions.        Grafting Antigen-Binding Domains into Alternative Frameworks or        Scaffolds

With respect to anti-FXI/FXIa antibody binding agents provided hereinwhich are antibodies, a wide variety of antibody/immunoglobulinframeworks or scaffolds can be employed so long as the resultingpolypeptide includes at least one binding region which specificallybinds to a target anti-FXI/FXIa antibody. Such frameworks or scaffoldsinclude the 5 main idiotypes of human immunoglobulins, or fragmentsthereof, and include immunoglobulins of other animal species, preferablyhaving humanized aspects. Single heavy-chain antibodies such as thoseidentified in camelids are of particular interest in this regard.

In one aspect, the present disclosure pertains to generatingnon-immunoglobulin based antibodies using non-immunoglobulin scaffoldsonto which CDRs such as those described in Table 2 can be grafted. Knownor future non-immunoglobulin frameworks and scaffolds may be employed,as long as they comprise a binding region specific for the targetanti-FXI/FXIa antibody such as NOV1401. Known non-immunoglobulinframeworks or scaffolds include, but are not limited to, fibronectin(Compound Therapeutics, Inc., Waltham, Mass.), ankyrin (MolecularPartners AG, Zurich, Switzerland), domain antibodies (Domantis, Ltd.,Cambridge, Mass., and Ablynx nv, Zwijnaarde, Belgium), lipocalin (PierisProteolab AG, Freising, Germany), small modular immuno-pharmaceuticals(Trubion Pharmaceuticals Inc., Seattle, Wash.), maxybodies (Avidia,Inc., Mountain View, Calif.), Protein A (Affibody AG, Sweden), andaffilin (gamma-crystallin or ubiquitin) (Scil Proteins GmbH, Halle,Germany).

The fibronectin scaffolds are based on fibronectin type III domain(e.g., the tenth module of the fibronectin type III (10 Fn3 domain)).The fibronectin type III domain has 7 or 8 beta strands which aredistributed between two beta sheets, which themselves pack against eachother to form the core of the protein, and further containing loops(analogous to CDRs) which connect the beta strands to each other and aresolvent exposed. There are at least three such loops at each edge of thebeta sheet sandwich, where the edge is the boundary of the proteinperpendicular to the direction of the beta strands (see U.S. Pat. No.6,818,418). These fibronectin-based scaffolds are not an immunoglobulin,although the overall fold is closely related to that of the smallestfunctional antibody fragment, the variable region of the heavy chain,which comprises the entire antigen recognition unit in camel and llamaIgG. Because of this structure, the non-immunoglobulin antibody mimicsantigen binding properties that are similar in nature and affinity tothose of antibodies. These scaffolds can be used in a loop randomizationand shuffling strategy in vitro that is similar to the process ofaffinity maturation of antibodies in vivo. These fibronectin-basedmolecules can be used as scaffolds where the loop regions of themolecule can be replaced with CDRs of the invention using standardcloning techniques.

The ankyrin technology is based on using proteins with ankyrin derivedrepeat modules as scaffolds for bearing variable regions which can beused for binding to different targets. The ankyrin repeat module is a 33amino acid polypeptide consisting of two anti-parallel α-helices and aβ-turn. Binding of the variable regions is mostly optimized by usingribosome display.

Avimers are derived from natural A-domain containing protein such asLRP-1. These domains are used by nature for protein-protein interactionsand in human over 250 proteins are structurally based on A-domains.Avimers consist of a number of different “A-domain” monomers (2-10)linked via amino acid linkers. Avimers can be created that can bind tothe target antigen using the methodology described in, for example, U.S.Patent Application Publication Nos. 20040175756; 20050053973;20050048512; and 20060008844.

Affibody affinity ligands are small, simple proteins composed of athree-helix bundle based on the scaffold of one of the IgG-bindingdomains of Protein A. Protein A is a surface protein from the bacteriumStaphylococcus aureus. This scaffold domain consists of 58 amino acids,13 of which are randomized to generate affibody libraries with a largenumber of ligand variants (See e.g., U.S. Pat. No. 5,831,012). Affibodymolecules mimic antibodies, they have a molecular weight of 6 kDa,compared to the molecular weight of antibodies, which is 150 kDa. Inspite of its small size, the binding site of affibody molecules issimilar to that of an antibody.

Anticalins are products developed by the company Pieris ProteoLab AG.They are derived from lipocalins, a widespread group of small and robustproteins that are usually involved in the physiological transport orstorage of chemically sensitive or insoluble compounds. Several naturallipocalins occur in human tissues or body liquids. The proteinarchitecture is reminiscent of immunoglobulins, with hypervariable loopson top of a rigid framework. However, in contrast with antibodies ortheir recombinant fragments, lipocalins are composed of a singlepolypeptide chain with 160 to 180 amino acid residues, being justmarginally bigger than a single immunoglobulin domain. The set of fourloops, which makes up the binding pocket, shows pronounced structuralplasticity and tolerates a variety of side chains. The binding site canthus be reshaped in a proprietary process in order to recognizeprescribed target molecules of different shape with high affinity andspecificity. One protein of lipocalin family, the bilin-binding protein(BBP) of Pieris brassicae has been used to develop anticalins bymutagenizing the set of four loops. One example of a patent applicationdescribing anticalins is in PCT Publication No. WO 199916873.

Affilin molecules are small non-immunoglobulin proteins which aredesigned for specific affinities towards proteins and small molecules.New affilin molecules can be very quickly selected from two libraries,each of which is based on a different human derived scaffold protein.Affilin molecules do not show any structural homology to immunoglobulinproteins. Currently, two affilin scaffolds are employed, one of which isgamma crystalline, a human structural eye lens protein and the other is“ubiquitin” superfamily proteins. Both human scaffolds are very small,show high temperature stability and are almost resistant to pH changesand denaturing agents. This high stability is mainly due to the expandedbeta sheet structure of the proteins. Examples of gamma crystallinederived proteins are described in WO200104144 and examples of“ubiquitin-like” proteins are described in WO2004106368.

Protein epitope mimetics (PEM) are medium-sized, cyclic, peptide-likemolecules (MW 1-2kDa) mimicking beta-hairpin secondary structures ofproteins, the major secondary structure involved in protein-proteininteractions.

In specific aspects, the present disclosure provides fully humanantibodies that specifically bind to a target anti-FXI/FXIa antibodysuch as NOV1401. Compared to the chimeric or humanized antibodies, humanantibodies have further reduced antigenicity when administered to humansubjects.

Bispecific Molecules and Multivalent Antibodies

In another aspect, the present disclosure features bispecific ormultispecific molecules comprising an antibody or a fragment thereofwhich specifically binds a target anti-FXI/FXIa antibody such as NOV1401and reverses one or more anticoagulant effects. An antibody providedherein, or antigen-binding regions thereof, can be derivatized or linkedto another functional molecule, e.g., another peptide or protein (e.g.,another antibody or ligand for a receptor) to generate a bispecificmolecule that binds to at least two different binding sites or targetmolecules. The antibody of the invention may in fact be derivatized orlinked to more than one other functional molecule to generatemulti-specific molecules that bind to more than two different bindingsites and/or target molecules; such multi-specific molecules are alsointended to be encompassed by the term “bispecific molecule” as usedherein. To create a bispecific molecule of the invention, an antibody ofthe invention can be functionally linked (e.g., by chemical coupling,genetic fusion, noncovalent association or otherwise) to one or moreother binding molecules, such as another antibody, antibody fragment,peptide or binding mimetic, such that a bispecific molecule results.

Accordingly, the present disclosure includes bispecific moleculescomprising at least one first binding specificity for a targetanti-FXI/FXIa antibody such as NOV1401, and a second binding specificityfor a second target epitope. For example, the second target epitope isanother epitope of an anti-FXI/FXIa antibody different from the firsttarget epitope.

Additionally, for aspects in which the bispecific molecule ismulti-specific, the molecule can further include a third bindingspecificity, in addition to the first and second target epitope.

In one aspect, bispecific molecules of the present disclosure compriseas a binding specificity at least one antibody, or an antibody fragmentthereof, including, e.g., a Fab, Fab′, F(ab′)2, Fv, or a single chainFv. The antibody may also be a light chain or heavy chain dimer, or anyminimal fragment thereof such as a Fv or a single chain construct asdescribed in Ladner et al. U.S. Pat. No. 4,946,778.

Diabodies are bivalent, bispecific molecules in which VH and VL domainsare expressed on a single polypeptide chain, connected by a linker thatis too short to allow for pairing between the two domains on the samechain. The VH and VL domains pair with complementary domains of anotherchain, thereby creating two antigen binding sites (see e.g., Holliger etal., 1993 Proc. Natl. Acad. Sci. USA 90:6444-6448; Poljak et al., 1994Structure 2:1121-1123). Diabodies can be produced by expressing twopolypeptide chains with either the structure VHA-VLB and VHB-VLA (VH-VLconfiguration), or VLA-VHB and VLB-VHA (VL-VH configuration) within thesame cell. Most of them can be expressed in soluble form in bacteria.Single chain diabodies (scDb) are produced by connecting the twodiabody-forming polypeptide chains with linker of approximately 15 aminoacid residues (see Holliger and Winter, 1997 Cancer Immunol.Immunother., 45(3-4):128-30; Wu et al., 1996 Immunotechnology,2(1):21-36). scDb can be expressed in bacteria in soluble, activemonomeric form (see Holliger and Winter, 1997 Cancer Immunol.Immunother., 45(34): 128-30; Wu et al., 1996 Immunotechnology,2(1):21-36; Pluckthun and Pack, 1997 Immunotechnology, 3(2): 83-105;Ridgway et al., 1996 Protein Eng., 9(7):617-21). A diabody can be fusedto Fc to generate a “di-diabody” (see Lu et al., 2004 J. Biol. Chem.,279(4):2856-65).

Other antibodies which can be employed in the bispecific molecules aremurine, chimeric and humanized monoclonal antibodies.

Bispecific molecules can be prepared by conjugating the constituentbinding specificities, using methods known in the art. For example, eachbinding specificity of the bispecific molecule can be generatedseparately and then conjugated to one another. When the bindingspecificities are proteins or peptides, a variety of coupling orcross-linking agents can be used for covalent conjugation. Examples ofcross-linking agents include protein A, carbodiimide,N-succinimidyl-S-acetyl-thioacetate (SATA),5,5′-dithiobis(2-nitrobenzoic acid) (DTNB), o-phenylenedimaleimide(oPDM), N-succinimidyl-3-(2-pyridyldithio)propionate (SPDP), andsulfosuccinimidyl 4-(N-maleimidomethyl) cyclohaxane-l-carboxylate(sulfo-SMCC) (see e.g., Karpovsky et al., 1984 J. Exp. Med. 160:1686;Liu, M A et al., 1985 Proc. Natl. Acad. Sci. USA 82:8648). Other methodsinclude those described in Paulus, 1985 Behring Ins. Mitt. No.78,118-132; Brennan et al., 1985 Science 229:81-83), and Glennie et al.,1987 J. Immunol. 139: 2367-2375). Conjugating agents are SATA andsulfo-SMCC, both available from Pierce Chemical Co. (Rockford, Ill.).

When the binding specificities are antibodies, they can be conjugated bysulfhydryl bonding of the C-terminus hinge regions of the two heavychains. In a particularly embodiment, the hinge region is modified tocontain an odd number of sulfhydryl residues, for example one, prior toconjugation.

Alternatively, both binding specificities can be encoded in the samevector and expressed and assembled in the same host cell. This method isparticularly useful where the bispecific molecule is a mAb×mAb, mAb×Fab,Fab×F(ab′)2 or ligand×Fab fusion protein. A bispecific molecule of theinvention can be a single chain molecule comprising one single chainantibody and a binding determinant, or a single chain bispecificmolecule comprising two binding determinants. Bispecific molecules maycomprise at least two single chain molecules. Methods for preparingbispecific molecules are described for example in U.S. Pat. Nos.5,260,203; 5,455,030; 4,881,175; 5,132,405; 5,091,513; 5,476,786;5,013,653; 5,258,498; and 5,482,858.

Binding of the bispecific molecules to their specific targets can beconfirmed by, for example, enzyme-linked immunosorbent assay (ELISA),radioimmunoassay (REA), FACS analysis, bioassay (e.g., growthinhibition), or Western Blot assay. Each of these assays generallydetects the presence of protein-antibody complexes of particularinterest by employing a labeled reagent (e.g., an antibody) specific forthe complex of interest.

In another aspect, the present invention provides multivalent compoundscomprising at least two identical or different antigen-binding portionsof the antibodies of the invention binding to FXIa. The antigen-bindingportions can be linked together via protein fusion or covalent ornon-covalent linkage. Alternatively, methods of linkage have beendescribed for the bispecific molecules. Tetravalent compounds can beobtained for example by cross-linking antibodies of the antibodies ofthe invention with an antibody that binds to the constant regions of theantibodies of the invention, for example the Fc or hinge region.

Trimerizing domain are described for example in Borean patent EP 1 012280B1. Pentamerizing modules are described for example inPCT/EP97/05897.

Antibody Conjugates and Fusions

In specific aspects, the present disclosure provides binding agents,which are antibodies or fragments thereof that specifically bind to atarget anti-FXI/FXIa antibody (e.g., such as NOV1401), and that arerecombinantly fused or chemically conjugated (including both covalentand non-covalent conjugations) to a heterologous protein or polypeptide(or fragment thereof. In a particular aspect, a heterologous protein isa polypeptide of at least 10, at least 20, at least 30, at least 40, atleast 50, at least 60, at least 70, at least 80, at least 90 or at least100 amino acids) is used to generate fusion proteins. In particularaspects, the present disclosure provides binding agents that are fusionproteins comprising an antigen-binding fragment of an antibody describedherein (e.g., a Fab fragment, Fd fragment, Fv fragment, F(ab)2 fragment,a VH domain, a VH CDR, a VL domain or a VL CDR) and a heterologousprotein, polypeptide, or peptide. Methods for fusing or conjugatingproteins, polypeptides, or peptides to an antibody or an antibodyfragment are known in the art. See, e.g., U.S. Pat. Nos. 5,336,603,5,622,929, 5,359,046, 5,349,053, 5,447,851, and 5,112,946; EuropeanPatent Nos. EP 307,434 and EP 367,166; International Publication Nos. WO96/04388 and WO 91/06570; Ashkenazi et al., 1991, Proc. Natl. Acad. Sci.USA 88: 10535-10539; Zheng et al., 1995, J. Immunol. 154:5590-5600; andVil et al., 1992, Proc. Natl. Acad. Sci. USA 89:11337-11341.

Additional fusion proteins may be generated through the techniques ofgene-shuffling, motif-shuffling, exon-shuffling, and/or codon-shuffling(collectively referred to as “DNA shuffling”). DNA shuffling may beemployed to alter the activities of antibodies of the invention orfragments thereof (e.g., antibodies or fragments thereof with higheraffinities and lower dissociation rates). See, generally, U.S. Pat. Nos.5,605,793, 5,811,238, 5,830,721, 5,834,252, and 5,837,458; Patten etal., 1997, Curr. Opinion Biotechnol. 8:724-33; Harayama, 1998, TrendsBiotechnol. 16(2):76-82; Hansson, et al., 1999, J. Mol. Biol.287:265-76; and Lorenzo and Blasco, 1998, Biotechniques 24(2):308-313(each of these patents and publications are hereby incorporated byreference in its entirety). Antibodies or fragments thereof, or theencoded antibodies or fragments thereof, may be altered by beingsubjected to random mutagenesis by error-prone PCR, random nucleotideinsertion or other methods prior to recombination. A polynucleotideencoding an antibody or fragment thereof that specifically binds to aFXIa protein may be recombined with one or more components, motifs,sections, parts, domains, fragments, etc. of one or more heterologousmolecules.

Moreover, the antibodies or fragments thereof can be fused to markersequences, such as a peptide to facilitate purification. In particularembodiments, the marker amino acid sequence is a hexa-histidine peptide,such as the tag provided in a pQE vector (QIAGEN, Inc., 9259 EtonAvenue, Chatsworth, Calif., 91311), among others, many of which arecommercially available. As described in Gentz et al., 1989, Proc. Natl.Acad. Sci. USA 86:821-824, for instance, hexa-histidine provides forconvenient purification of the fusion protein. Other peptide tags usefulfor purification include, but are not limited to, the hemagglutinin(“HA”) tag, which corresponds to an epitope derived from the influenzahemagglutinin protein (Wilson et al., 1984, Cell 37:767), and the “flag”tag.

In other aspects, binding agents such as antibodies described herein orfragments thereof are conjugated to a compound, for example, adiagnostic or detectable agent. In one aspect, such antibodies orfragments thereof are conjugated by coupling the antibody to detectablesubstances including, but not limited to, various enzymes, such as, butnot limited to, horseradish peroxidase, alkaline phosphatase,beta-galactosidase, or acetylcholinesterase; prosthetic groups, such as,but not limited to, streptavidinlbiotin and avidin/biotin; fluorescentmaterials, such as, but not limited to, umbelliferone, fluorescein,fluorescein isothiocynate, rhodamine, dichlorotriazinylaminefluorescein, dansyl chloride or phycoerythrin; luminescent materials,such as, but not limited to, luminol; bioluminescent materials, such asbut not limited to, luciferase, luciferin, and aequorin; radioactivematerials, such as, but not limited to, iodine (131I, 125I, 123I, and121I,), carbon (14C), sulfur (35S), tritium (3H), indium (115In, 113In,112In, and 111In,), technetium (99Tc), thallium (201Ti), gallium (68Ga,67Ga), palladium (103Pd), molybdenum (99Mo), xenon (133Xe), fluorine(18F), 153Sm, 177Lu, 159Gd, 149Pm, 140La, 175Yb, 166Ho, 90Y, 47Sc,186Re, 188Re,142 Pr, 105Rh, 97Ru, 68Ge, 57Co, 65Zn, 85Sr, 32P, 153Gd,169Yb, 51Cr, 54Mn, 75Se, 113Sn, and 117Tin; and positron emitting metalsusing various positron emission tomographies, and noradioactiveparamagnetic metal ions.

Further, an antibody or fragment thereof may be conjugated to atherapeutic moiety or drug moiety that modifies a given biologicalresponse. Therapeutic moieties or drug moieties are not to be construedas limited to classical chemical therapeutic agents. For example, thedrug moiety may be a protein, peptide, or polypeptide possessing adesired biological activity.

Techniques for conjugating therapeutic moieties to antibodies are wellknown, see, e.g., Arnon et al., “Monoclonal Antibodies ForImmunotargeting Of Drugs In Cancer Therapy”, in Monoclonal AntibodiesAnd Cancer Therapy, Reisfeld et al. (eds.), pp. 243-56 (Alan R. Liss,Inc. 1985); Hellstrom et al., “Antibodies For Drug Delivery”, inControlled Drug Delivery (2nd Ed.), Robinson et al. (eds.), pp. 623-53(Marcel Dekker, Inc. 1987); Thorpe, “Antibody Carriers Of CytotoxicAgents In Cancer Therapy: A Review”, in Monoclonal Antibodies 84:Biological And Clinical Applications, Pinchera et al. (eds.), pp.475-506 (1985); “Analysis, Results, And Future Prospective Of TheTherapeutic Use Of Radiolabeled Antibody In Cancer Therapy”, inMonoclonal Antibodies For Cancer Detection And Therapy, Baldwin et al.(eds.), pp. 303-16 (Academic Press 1985), and Thorpe et al., 1982,Immunol. Rev. 62:119-58.

Antibodies may also be attached to solid supports, which areparticularly useful for immunoassays or purification of the targetantigen. Such solid supports include, but are not limited to, glass,cellulose, polyacrylamide, nylon, polystyrene, polyvinyl chloride orpolypropylene.

Methods of Producing Antibodies

Provided herein are nucleic acid molecules (e.g., substantially purifiednucleic acid molecules) which encode polypeptides of binding agentsdescribed herein, vectors (e.g., expression vectors) comprising thesame, host cells comprising such vectors or nucleic acid molecules, andmethods of producing binding agents described herein, e.g., antibodiesor antigen-binding fragment thereof, such as Fab fragments, whichspecifically binds an anti-FXI/FXIa antibody, e.g., NOV1401.

In specific aspects, provided herein is a vector (e.g., expressionvector) comprising a polynucleotide described herein (e.g., Table 2).

In certain aspects, provided herein is a host cell comprising a vectordescribed herein or a polynucleotide described herein. In specificaspects, the host cell is a eukaryotic cell. In certain aspects, thehost cell is a mammalian cell (e.g., non-human mammalian cell, such asCHO cells). In particular aspects, a host cell comprises (i) a vector orpolynucleotide comprising nucleotide sequences encoding a VH or a heavychain and (ii) a vector or polynucleotide comprising nucleotidesequences encoding a VL or a light chain. In specific aspects, a firsthost cell comprises a vector or polynucleotide comprising nucleotidesequences encoding a VH or a heavy chain and a second host cellcomprises a vector or polynucleotide comprising nucleotide sequencesencoding a VL or a light chain.

In particular aspects, provided herein is a method of producing abinding agent, e.g., an antibody or antigen-binding fragment (e.g., Fabfragment) that binds an anti-FXI/FXIa antibody, such as NOV1401,comprising the step of culturing a host cell described herein underconditions suitable for expression of the binding agent.

In certain aspects, the method of producing an anti-FXI/FXIa antibody orfragment thereof further comprises purifying the anti-FXI/FXIa antibodyor fragment thereof.

Nucleic Acids Encoding Binding Agents

The present disclosure provides polynucleotides comprising nucleotidesequences encoding binding agents described herein. In specific aspects,the present disclosure provides polynucleotides comprising nucleic acidsequences that encode the VH, VL, full length heavy chain, and/or fulllength light chain of antibodies described herein that specifically bindto a target anti-FXI/FXIa antibody, for example, antibodies IDT1, IDT2,IDT3, IDT4, IDT5, IDT6, IDT7, IDT8, IDT9, and IDT10. Such nucleic acidsequences can be optimized for expression in mammalian cells (forexample, see Table 2).

In specific aspects where a binding agent is an antibody orantigen-binding fragment thereof, provided herein is a polynucleotidecomprising nucleotide sequences encoding a VL, VH or a VL and VH of ananti-FXI/FXIa antibody binding agent described herein, e.g., antibodyIDT1, IDT2, IDT3, IDT4, IDT5, IDT6, IDT7, IDT8, IDT9, or IDT10. In oneaspect, a polynucleotide provided herein comprises a nucleotide sequenceencoding a VL of an anti-FXI/FXIa antibody binding agent describedherein, e.g., antibody IDT1, IDT2, IDT3, IDT4, IDT5, IDT6, IDT7, IDT8,IDT9, or IDT10. In one aspect, a polynucleotide provided hereincomprises a nucleotide sequence encoding a VH of an anti-FXI/FXIaantibody binding agent described herein, e.g., antibody IDT1, IDT2,IDT3, IDT4, IDT5, IDT6, IDT7, IDT8, IDT9, or IDT10. In one aspect, apolynucleotide provided herein comprises a nucleotide sequence encodinga VH and a VL of an anti-FXI/FXIa antibody binding agent describedherein, e.g., antibody IDT1, IDT2, IDT3, IDT4, IDT5, IDT6, IDT7, IDT8,IDT9, or IDT10.

In specific aspects where a binding agent is an antibody orantigen-binding fragment thereof, provided herein is a polynucleotidecomprising nucleotide sequences encoding a heavy chain, a light chain,or a heavy chain and a light chain of an anti-FXI/FXIa antibody bindingagent described herein, e.g., antibody IDT1, IDT2, IDT3, IDT4, IDT5,IDT6, IDT7, IDT8, IDT9, or IDT10. In one aspect, a polynucleotideprovided herein comprises a nucleotide sequence encoding a heavy chainof an anti-FXI/FXIa antibody binding agent described herein, e.g.,antibody IDT1, IDT2, IDT3, IDT4, IDT5, IDT6, IDT7, IDT8, IDT9, or IDT10.In one aspect, a polynucleotide provided herein comprises a nucleotidesequence encoding a light chain of an anti-FXI/FXIa antibody bindingagent described herein, e.g., antibody IDT1, IDT2, IDT3, IDT4, IDT5,IDT6, IDT7, IDT8, IDT9, or IDT10. In one aspect, a polynucleotideprovided herein comprises a nucleotide sequence encoding a heavy chainand a light chain of an anti-FXI/FXIa antibody binding agent describedherein, e.g., antibody IDT1, IDT2, IDT3, IDT4, IDT5, IDT6, IDT7, IDT8,IDT9, or IDT10.

In particular aspects, provided herein is a polynucleotide comprisingone or more nucleotide sequences set forth in Table 2, for example, apolynucleotide comprising the nucleotide sequence of SEQ ID NO: 40, 72,104, 136, 168, 200, 232, 264, 296, or 328 encoding a VH; and acomprising the nucleotide sequence of SEQ ID NO: 56, 88, 120, 152, 184,216, 248, 280, 312, or 344 encoding a VL.

In particular aspects, provided herein is a polynucleotide comprisingone or more nucleotide sequences set forth in Table 2, for example, apolynucleotide comprising the nucleotide sequence of SEQ ID NO: 42, 74,106, 138, 170, 202, 234, 266, 298, or 330 encoding a heavy chain; and acomprising the nucleotide sequence of SEQ ID NO: 58, 90, 122, 154, 186,218, 250, 282, 314, or 346 encoding a light chain.

In certain aspects, polynucleotides provided herein comprise nucleotidesequences that are substantially identical (e.g., at least 65%, 80%,80%, 90%, 95%, 98%, or 99%) to the nucleotide sequences of thoseidentified in Table 2, for example, SEQ ID NO: 40, 72, 104, 136, 168,200, 232, 264, 296, or 328 encoding a VH; and SEQ ID NO: 56, 88, 120,152, 184, 216, 248, 280, 312, or 344 encoding a VL. When expressed fromappropriate expression vectors, polypeptides encoded by thesepolynucleotides are capable of binding to an anti-FXI/FXIa antibody,such as antibody NOV1401.

Also provided in the present disclosure are polynucleotides which encodeat least one CDR region and usually all three CDR regions from a heavyor light chain variable region of a binding agent described herein(e.g., Table 2), e.g., binding agent which is an antibody orantigen-binding fragment thereof that binds an anti-FXI/FXIa antibody.In other aspects, some polynucleotides encode all or substantially allof the variable region sequence of a heavy chain and/or a light chain ofa binding agent described herein (e.g., Table 2), e.g., binding agentwhich is an antibody or antigen-binding fragment thereof that binds ananti-FXI/FXIa antibody. In specific aspects, provided herein arepolynucleotides which can encode both a variable region and a constantregion of an antibody, e.g., an antibody or antigen-binding fragmentthereof that binds an anti-FXI/FXIa antibody. Because of the degeneracyof the code, a variety of nucleic acid sequences will encode each of theimmunoglobulin amino acid sequences.

Polynucleotide sequences can be produced by de novo solid-phase DNAsynthesis or by PCR mutagenesis of an existing sequence (e.g., sequencesas described herein) encoding a binding agent, e.g., a binding agentwhich is an antibody or antigen-binding fragment there of (e.g., Fabfragment) that binds an anti-FXI/FXIa-antibody. Direct chemicalsynthesis of nucleic acids can be accomplished by methods known in theart, such as the phosphotriester method of Narang et al., 1979, Meth.Enzymol. 68:90; the phosphodiester method of Brown et al., Meth.Enzymol. 68:109, 1979; the diethylphosphoramidite method of Beaucage etal., Tetra. Lett., 22:1859, 1981; and the solid support method of U.S.Pat. No. 4,458,066. Introducing mutations to a polynucleotide sequenceby PCR can be performed as described in, e.g., PCR Technology:Principles and Applications for DNA Amplification, H. A. Erlich (Ed.),Freeman Press, NY, NY, 1992; PCR Protocols: A Guide to Methods andApplications, Innis et al. (Ed.), Academic Press, San Diego, Calif.,1990; Mattila et al., Nucleic Acids Res. 19:967, 1991; and Eckert etal., PCR Methods and Applications 1:17, 1991.

Also provided in the present disclosure are expression vectors and hostcells for producing a binding agent described herein, e.g., a bindingagent which is an antibody or antigen-binding fragment there of (e.g.,Fab fragment) that binds an anti-FXI/FXIa-antibody. Various expressionvectors can be employed to express the polynucleotides encoding theFXIa-binding antibody chains or binding fragments. Both viral-based andnonviral expression vectors can be used to produce the antibodies in amammalian host cell. Nonviral vectors and systems include plasmids,episomal vectors, typically with an expression cassette for expressing aprotein or RNA, and human artificial chromosomes (see, e.g., Harringtonet al., Nat Genet 15:345, 1997). For example, nonviral vectors usefulfor expression of polynucleotides and polypeptides in mammalian (e.g.,human) cells include pThioHis A, B & C, pcDNA3.1/His, pEBVHis A, B & C,(Invitrogen, San Diego, Calif.), MPSV vectors, and numerous othervectors known in the art for expressing other proteins. Useful viralvectors include vectors based on retroviruses, adenoviruses,adenoassociated viruses, herpes viruses, vectors based on SV40,papilloma virus, HBP Epstein Barr virus, vaccinia virus vectors andSemliki Forest virus (SFV). See, Brent et al., supra; Smith, Annu. Rev.Microbiol. 49:807, 1995; and Rosenfeld et al., Cell 68:143, 1992.

The choice of expression vector depends on the intended host cells inwhich the vector is to be expressed. Typically, the expression vectorscontain a promoter and other regulatory sequences (e.g., enhancers) thatare operably linked to the polynucleotides encoding a binding agentdescribed herein, e.g., a binding agent which is an antibody orantigen-binding fragment there of (e.g., Fab fragment) that binds ananti-FXI/FXIa-antibody, such as NOV1401. In some embodiments, aninducible promoter is employed to prevent expression of insertedsequences except under inducing conditions. Inducible promoters include,e.g., arabinose, lacZ, metallothionein promoter or a heat shockpromoter. Cultures of transformed organisms can be expanded undernoninducing conditions without biasing the population for codingsequences whose expression products are better tolerated by the hostcells. In addition to promoters, other regulatory elements may also berequired or desired for efficient expression of a binding agent, e.g., abinding agent which is an antibody or antigen-binding fragment there of(e.g., Fab fragment) that binds an anti-FXI/FXIa-antibody, such asNOV1401. These elements typically include an ATG initiation codon andadjacent ribosome binding site or other sequences. In addition, theefficiency of expression may be enhanced by the inclusion of enhancersappropriate to the cell system in use (see, e.g., Scharf et al., ResultsProbl. Cell Differ. 20:125, 1994; and Bittner et al., Meth. Enzymol.,153:516, 1987). For example, the SV40 enhancer or CMV enhancer may beused to increase expression in mammalian host cells.

The expression vectors may also provide a secretion signal sequenceposition to form a fusion protein with polypeptides encoded by insertedanti-FXI/FXIa-antibody binding agent sequences. In specific aspects,inserted anti-FXI/FXIa-antibody binding agent sequences are linked to asignal sequences before inclusion in the vector. Vectors to be used toreceive sequences encoding anti-FXI/FXIa-antibody binding agent (e.g.,antibody NOV1401 binding agent) light and heavy chain variable domains,and in certain aspects, also encode constant regions or parts thereof.Such vectors allow expression of the variable regions as fusion proteinswith the constant regions thereby leading to production of intactantibodies or fragments thereof. Typically, such constant regions arehuman.

Host cells for harboring and expressing an anti-FXI/FXIa-antibodybinding agent (e.g., antibody NOV1401 binding agent) can be eitherprokaryotic or eukaryotic. E. coli is one prokaryotic host useful forcloning and expressing the polynucleotides of the present disclosure.Other microbial hosts suitable for use include bacilli, such as Bacillussubtilis, and other enterobacteriaceae, such as Salmonella, Serratia,and various Pseudomonas species. In these prokaryotic hosts, one canalso make expression vectors, which typically contain expression controlsequences compatible with the host cell (e.g., an origin ofreplication). In addition, any number of a variety of well-knownpromoters will be present, such as the lactose promoter system, atryptophan (trp) promoter system, a beta-lactamase promoter system, or apromoter system from phage lambda. The promoters typically controlexpression, optionally with an operator sequence, and have ribosomebinding site sequences and the like, for initiating and completingtranscription and translation. Other microbes, such as yeast, can alsobe employed to express FXIa-binding polypeptides of the presentdisclosure. Insect cells in combination with baculovirus vectors canalso be used.

In some specific embodiments, mammalian host cells are used to expressand produce anti-FXI/FXIa-antibody binding agent (e.g., antibody NOV1401binding agent) polypeptides of the present disclosure. These include anynormal mortal or normal or abnormal immortal animal or human cell. Forexample, a number of suitable host cell lines capable of secretingintact immunoglobulins have been developed including the CHO cell lines,various Cos cell lines, HeLa cells, myeloma cell lines, and transformedB-cells. The use of mammalian tissue cell culture to expresspolypeptides is discussed generally in, e.g., Winnacker, FROM GENES TOCLONES, VCH Publishers, N.Y., N.Y., 1987. Expression vectors formammalian host cells can include expression control sequences, such asan origin of replication, a promoter, and an enhancer (see, e.g., Queen,et al., Immunol. Rev. 89:49-68, 1986), and necessary processinginformation sites, such as ribosome binding sites, RNA splice sites,polyadenylation sites, and transcriptional terminator sequences.

These expression vectors usually contain promoters derived frommammalian genes or from mammalian viruses. Suitable promoters may beconstitutive, cell type-specific, stage-specific, and/or modulatable orregulatable. Useful promoters include, but are not limited to, themetallothionein promoter, the constitutive adenovirus major latepromoter, the dexamethasone-inducible MMTV promoter, the SV40 promoter,the MRP polIII promoter, the constitutive MPSV promoter, thetetracycline-inducible CMV promoter (such as the human immediate-earlyCMV promoter), the constitutive CMV promoter, and promoter-enhancercombinations known in the art.

Methods for introducing expression vectors containing the polynucleotidesequences of interest vary depending on the type of cellular host. Forexample, calcium chloride transfection is commonly utilized forprokaryotic cells, whereas calcium phosphate treatment orelectroporation may be used for other cellular hosts. (See generallySambrook, et al., supra). Other methods include, e.g., electroporation,calcium phosphate treatment, liposome-mediated transformation, injectionand microinjection, ballistic methods, virosomes, immunoliposomes,polycation:nucleic acid conjugates, naked DNA, artificial virions,fusion to the herpes virus structural protein VP22 (Elliot and O'Hare,Cell 88:223, 1997), agent-enhanced uptake of DNA, and ex vivotransduction. For long-term, high-yield production of recombinantproteins, stable expression will often be desired. For example, celllines which stably express FXIa-binding antibody chains or bindingfragments can be prepared using expression vectors of the presentdisclosure which contain viral origins of replication or endogenousexpression elements and a selectable marker gene. Following theintroduction of the vector, cells may be allowed to grow for 1-2 days inan enriched media before they are switched to selective media. Thepurpose of the selectable marker is to confer resistance to selection,and its presence allows growth of cells which successfully express theintroduced sequences in selective media. Resistant, stably transfectedcells can be proliferated using tissue culture techniques appropriate tothe cell type.

Framework or Fc engineering

Engineered antibodies of the present disclosure include those in whichmodifications have been made to framework residues within VH and/or VL,e.g. to improve the properties of the antibody. Typically such frameworkmodifications are made to decrease the immunogenicity of the antibody.For example, one approach is to “backmutate” one or more frameworkresidues to the corresponding germline sequence. More specifically, anantibody that has undergone somatic mutation may contain frameworkresidues that differ from the germline sequence from which the antibodyis derived. Such residues can be identified by comparing the antibodyframework sequences to the germline sequences from which the antibody isderived. To return the framework region sequences to their germlineconfiguration, the somatic mutations can be “backmutated” to thegermline sequence by, for example, site-directed mutagenesis. Such“backmutated” antibodies are also intended to be encompassed by thepresent disclosure.

Another type of framework modification involves mutating one or moreresidues within the framework region, or even within one or more CDRregions, to remove T cell—epitopes to thereby reduce the potentialimmunogenicity of the antibody. This approach is also referred to as“deimmunization” and is described in further detail in U.S. PatentPublication No. 20030153043 by Carr et al.

In addition or alternative to modifications made within the framework orCDR regions, antibodies of the present disclosure may be engineered toinclude modifications within the Fc region, typically to alter one ormore functional properties of the antibody, such as serum half-life,complement fixation, Fc receptor binding, and/or antigen-dependentcellular cytotoxicity. Furthermore, an antibody of the presentdisclosure may be chemically modified (e.g., one or more chemicalmoieties can be attached to the antibody) or be modified to alter itsglycosylation, again to alter one or more functional properties of theantibody. Each of these embodiments is described in further detailbelow. The numbering of residues in the Fc region is that of the EUindex of Kabat.

In one aspect, the hinge region of CH1 is modified such that the numberof cysteine residues in the hinge region is altered, e.g., increased ordecreased. This approach is described further in U.S. Pat. No. 5,677,425by Bodmer et al. The number of cysteine residues in the hinge region ofCH1 is altered to, for example, facilitate assembly of the light andheavy chains or to increase or decrease the stability of the antibody.

In another aspect, the Fc hinge region of an antibody is mutated todecrease the biological half-life of the antibody. More specifically,one or more amino acid mutations are introduced into the CH2-CH3 domaininterface region of the Fc-hinge fragment such that the antibody hasimpaired Staphylococcyl protein A (SpA) binding relative to nativeFc-hinge domain SpA binding. This approach is described in furtherdetail in U.S. Pat. No. 6,165,745 by Ward et al.

In another aspect, the antibody is modified to increase its biologicalhalf-life. Various approaches are possible. For example, one or more ofthe mutations as described in U.S. Pat. No. 6,277,375 to Ward can beused. Alternatively, to increase the biological half-life, the antibodycan be altered within the CH1 or CL region to contain a salvage receptorbinding epitope taken from two loops of a CH2 domain of an Fc region ofan IgG, as described in U.S. Pat. Nos. 5,869,046 and 6,121,022 by Prestaet al.

In yet other aspects, the Fc region is altered by replacing at least oneamino acid residue with a different amino acid residue to alter theeffector functions of the antibody. For example, one or more amino acidscan be replaced with a different amino acid residue such that theantibody has an altered affinity for an effector ligand but retains theantigen-binding ability of the parent antibody. The effector ligand towhich affinity is altered can be, for example, an Fc receptor or the Clcomponent of complement. This approach is described in further detail inU.S. Pat. Nos. 5,624,821 and 5,648,260, both by Winter et al.

In another aspect, one or more amino acids selected from amino acidresidues can be replaced with a different amino acid residue such thatthe antibody has altered C1q binding and/or reduced or abolishedcomplement dependent cytotoxicity (CDC). This approach is described infurther detail in U.S. Pat. No. 6,194,551 by Idusogie et al.

In another aspect, one or more amino acid residues are altered tothereby alter the ability of the antibody to fix complement. Thisapproach is described further in PCT Publication WO 94/29351 by Bodmeret al.

In a specific aspect, a binding agent described herein (e.g., bindingagent described in Table 2), for example, a binding agent which is anantibody or antigen-binding fragment thereof (e.g., Fab fragment) thatbinds an anti-FXI/FXIa-antibody (such as antibody NOV1401) comprises ahuman IgG (e.g., IgG1) Fc region comprising amino acid substitutions,D265A and/or P329A, to reduce the likelihood for ADCC or CDC caused byany surface-associated FXI. These Alanine substitutions have been shownto reduce ADCC and CDC (see, e.g., Idosugie et al., J. Immunol.164:4178-4184, 2000; Shields et al., J. Biol. Chem. 276:6591-6604,2001).

In yet another aspect, the Fc region is modified to increase the abilityof the antibody to mediate antibody dependent cellular cytotoxicity(ADCC) and/or to increase the affinity of the antibody for an Fcγreceptor by modifying one or more amino acids. This approach isdescribed further in PCT Publication WO 00/42072 by Presta. Moreover,the binding sites on human IgG1 for FcγR1, FcγRII, FcγRIII and FcRn havebeen mapped and variants with improved binding have been described (seeShields, R. L. et al., 2001 J. Biol. Chen. 276:6591-6604).

In still another aspect, the glycosylation of an antibody is modified.For example, an aglycoslated antibody can be made (i.e., the antibodylacks glycosylation). Glycosylation can be altered to, for example,increase the affinity of the antibody for “antigen.” Such carbohydratemodifications can be accomplished by, for example, altering one or moresites of glycosylation within the antibody sequence. For example, one ormore amino acid substitutions can be made that result in elimination ofone or more variable region framework glycosylation sites to therebyeliminate glycosylation at that site. Such aglycosylation may increasethe affinity of the antibody for antigen. Such an approach is describedin further detail in U.S. Pat. Nos. 5,714,350 and 6,350,861 by Co et al.

Additionally or alternatively, an antibody can be made that has analtered type of glycosylation, such as a hypofucosylated antibody havingreduced amounts of fucosyl residues or an antibody having increasedbisecting GlcNac structures. Such altered glycosylation patterns havebeen demonstrated to increase the ADCC ability of antibodies. Suchcarbohydrate modifications can be accomplished by, for example,expressing the antibody in a host cell with altered glycosylationmachinery. Cells with altered glycosylation machinery have beendescribed in the art and can be used as host cells in which to expressrecombinant antibodies of the present disclosure to thereby produce anantibody with altered glycosylation. For example, EP 1,176,195 by Hanget al. describes a cell line with a functionally disrupted FUT8 gene,which encodes a fucosyl transferase, such that antibodies expressed insuch a cell line exhibit hypofucosylation. PCT Publication WO 03/035835by Presta describes a variant CHO cell line, Lecl3 cells, with reducedability to attach fucose to Asn(297)-linked carbohydrates, alsoresulting in hypofucosylation of antibodies expressed in that host cell(see also Shields, R. L. et al., 2002 J. Biol. Chem. 277:26733-26740).PCT Publication WO 99/54342 by Umana et al. describes cell linesengineered to express glycoprotein-modifying glycosyl transferases(e.g., beta(1,4)-N acetylglucosaminyltransferase III (GnTIII)) such thatantibodies expressed in the engineered cell lines exhibit increasedbisecting GlcNac structures which results in increased ADCC activity ofthe antibodies (see also Umana et al., 1999 Nat. Biotech. 17:176-180).

Methods of Engineering Altered Antibodies

As discussed above, binding agents described herein, for example,binding agents which are antibodies or antigen-binding fragment thereof(e.g., Fab fragment) that bind an anti-FXI/FXIa-antibody, such asNOV1401, and that VH and VL sequences or full length heavy and lightchain sequences provided herein (e.g., Table 2) can be used to createnew anti-FXI/FXIa-antibody binding agents (e.g., antibody NOV1401binding agents) by modifying full length heavy chain and/or light chainsequences, VH and/or VL sequences, or the constant region(s) attachedthereto. Thus, in another aspect of the present disclosure, thestructural features of an anti-FXI/FXIa-antibody binding agent of thepresent disclosure are used to create structurally relatedanti-FXI/FXIa-antibody binding agents that retain at least onefunctional property of the antibodies of the present disclosure, such asbinding to an anti-FXI/FXIa antibody, e.g., NOV1401, and also reversingone or more activities of an anti-FXI/FXIa antibody, e.g., reversing oneor more anticoagulant activities of an anti-FXI/FXIa antibody.

For example, one or more CDR regions of the antibodies of the presentdisclosure, or mutations thereof, can be combined recombinantly withknown framework regions and/or other CDRs to create additional,recombinantly-engineered, anti-FXI/FXIa antibody-binding agents (e.g.,antibody NOV1401 binding agent) of the present disclosure, as discussedabove. Other types of modifications include those described in theprevious section. The starting material for the engineering method isone or more of the VH and/or VL sequences provided herein, or one ormore CDR regions thereof. To create the engineered antibody, it is notnecessary to actually prepare (i.e., express as a protein) an antibodyhaving one or more of the VH and/or VL sequences provided herein, or oneor more CDR regions thereof. Rather, the information contained in thesequence(s) is used as the starting material to create a “secondgeneration” sequence(s) derived from the original sequence(s) and thenthe “second generation” sequence(s) is prepared and expressed as aprotein.

Accordingly, in another aspect, the present disclosure provides a methodfor preparing an anti-FXI/FXIa antibody binding agent (e.g., antibodyNOV1401 binding agent) optimized for expression in a mammalian cellconsisting of: a full length heavy chain antibody sequence having asequence selected from those provided in Table 2; and a full lengthlight chain antibody sequence having a sequence selected from thoseprovided in Table 2; altering at least one amino acid residue within thefull length heavy chain antibody sequence and/or the full length lightchain antibody sequence to create at least one altered antibodysequence; and expressing the altered antibody sequence as a protein. Inone embodiment, the alteration of the heavy or light chain is in theframework region of the heavy or light chain.

The altered antibody sequence can also be prepared by screening antibodylibraries having fixed CDR3 sequences or minimal essential bindingdeterminants as described in US2005/0255552 and diversity on CDR1 andCDR2 sequences. The screening can be performed according to anyscreening technology appropriate for screening antibodies from antibodylibraries, such as phage display technology.

Standard molecular biology techniques can be used to prepare and expressthe altered antibody sequence. The antibody encoded by the alteredantibody sequence(s) is one that retains one, some or all of thefunctional properties of anti-FXI/FXIa-antibody binding agents (e.g.,antibody NOV1401 binding agents) described herein, which functionalproperties include, but are not limited to, specifically binding ananti-FXI/FXIa antibody (e.g., antibody NOV1401), for example, andcontacting the one or more CDR amino acid residues of the anti-FXI/FXIa;inhibiting binding of a target anti-FXI/FXIa antibody (e.g., antibodyNOV1401) to human FXI and/or FXIa; inhibiting the ability of a targetanti-FXI/FXIa antibody (e.g., antibody NOV1401) to block the activity ofFXIa; and inhibiting or reversing one or more anticoagulant effects of atarget anti-FXI/FXIa antibody (e.g., antibody NOV1401).

In certain embodiments of the methods of engineering antibodies of thepresent disclosure, mutations can be introduced randomly or selectivelyalong all or part of an anti-FXI/FXIa antibody binding agent codingsequence and the resulting modified anti-FXI/FXIa antibody bindingagents can be screened for binding activity and/or other functionalproperties as described herein. Mutational methods have been describedin the art. For example, PCT Publication WO 02/092780 by Short describesmethods for creating and screening antibody mutations using saturationmutagenesis, synthetic ligation assembly, or a combination thereof.Alternatively, PCT Publication WO 03/074679 by Lazar et al. describesmethods of using computational screening methods to optimizephysiochemical properties of antibodies.

In certain aspects of the present disclosure anti-FXI/FXIa antibodybinding agents (e.g., antibody NOV1401 binding agent) have beenengineered to remove sites of deamidation. Deamidation is known to causestructural and functional changes in a peptide or protein. Deamindationcan result in decreased bioactivity, as well as alterations inpharmacokinetics and antigenicity of the protein pharmaceutical. (AnalChem. 2005 Mar. 1; 77(5):1432-9).

In certain aspects of the present disclosure anti-FXI/FXIa antibodybinding agents (e.g., antibody NOV1401 binding agent) described hereinhave been engineered to increase pI and improve their drug-likeproperties. The pI of a protein is a key determinant of the overallbiophysical properties of a molecule. Antibodies and polypeptides thathave low pIs have been known to be less soluble, less stable, and proneto aggregation. Further, the purification of antibodies and polypeptideswith low pI is challenging and can be problematic especially duringscale-up for clinical use. Increasing the pI of binding agents, such asantibodies, or Fabs, of the present disclosure improved theirsolubility, enabling the antibodies to be formulated at higherconcentrations (>100 mg/ml). Formulation of the antibodies at highconcentrations (e.g. >100 mg/ml) offers the advantage of being able toadminister higher doses of the antibodies, which in turn may enablereduced dosing frequency, a significant advantage for treatment ofchronic diseases including thrombotic and/or thromboembolic disorders.Higher pIs may also increase the FcRn-mediated recycling of the IgGversion of the antibody thus enabling the drug to persist in the bodyfor a longer duration, requiring fewer injections. Finally, the overallstability of the antibodies is significantly improved due to the higherpI resulting in longer shelf-life and bioactivity in vivo. In specificaspects, the pI of an anti-FXI/FXIa antibody binding agent is greaterthan or equal to 8.2.

The functional properties of the altered antibodies can be assessedusing standard assays available in the art and/or described herein, suchas those set forth in the Examples (e.g., ELISAs, aPTT assay, TGAassay).

Prophylactic and Therapeutic Uses

The present disclosure relates to methods for reversing (e.g., partiallyreversing) or decreasing the anticoagulant effect of an anti-FXI/FXIaantibody (e.g., antibody NOV1401) in a patient being treated with theanti-FXI/FXIa antibody or antigen-binding fragment thereof, comprisingadministering an effective amount of a binding agent provided herein,e.g., a binding agent (e.g., antibody or antigen-binding fragmentthereof, such as a Fab fragment) which binds an anti-FXI/FXIa antibodyand is capable of reversing one or more anticoagulant effects. Inspecific aspects, reversal of the anticoagulant effects of ananti-FXI/FXIa antibody may be needed by a patient for emergencysurgery/urgent procedures and in life-threatening or uncontrolledbleeding. In particular aspects, a patient is being treated with ananti-FXI/FXIa antibody to manage, treat, prevent, or reduce the risk ofa thromboembolic disease or disorder, for example reducing the risk ofstroke or thrombosis (e.g., systemic embolism) in patients with atrialfibrillation (e.g., non-valvular atrial fibrillation), chronic kidneydisease, such as end stage renal failure (ESRD) undergoing hemodialysis.In further specific aspects, the patient has a demonstrated high risk ofbleeding. In specific aspects, non-limiting examples of anti-FXI/FXIaantibody binding agents for use in these methods include antibodies(e.g., anti-idiotype antibodies) and antigen-binding fragments, such asFab fragments, described herein, e.g., in Table 2, for example,antibodies IDT1, IDT2, IDT3, IDT4, IDT5, IDT6, IDT7, IDT8, IDT9, andIDT10; antibodies comprising VH CDRs and VL CDRs of such antibodies;antibodies that bind the same epitope(s) within target antibody NOV1401as such antibodies.

In certain aspects, the present disclosure relates to methods forreducing clotting time in a subject administered an anti-FXI/FXIaantibody (e.g., antibody NOV1401), comprising administering an effectiveamount of a binding agent provided herein, e.g., a binding agent (e.g.,anti-idiotype antibody or antigen-binding fragment thereof, such as aFab fragment) which binds the anti-FXI/FXIa antibody and is capable ofinhibiting binding of the anti-FXI/FXIa antibody to human FXI/FXIa.

In specific aspects, the present disclosure relates to methods formanaging bleeding or bleeding risk or for reducing bleeding or bleedingrisk in a patient being treated with an anti-FXI/FXIa antibody (e.g.,antibody NOV1401), comprising administering an effective amount of abinding agent provided herein, e.g., a binding agent (e.g., antibody orantigen-binding fragment thereof, such as a Fab fragment) which binds ananti-FXI/FXIa antibody and is capable of reversing one or moreanticoagulant effects. In specific aspects, reversal of theanticoagulant effects of an anti-FXI/FXIa antibody may be needed by apatient for emergency surgery/urgent procedures and in life-threateningor uncontrolled bleeding. In particular aspects, a patient is beingtreated with an anti-FXI/FXIa antibody to manage, treat, prevent, orreduce the risk of a thromboembolic disease or disorder, for examplereducing the risk of stroke or thrombosis (e.g., systemic embolism) inpatients with atrial fibrillation (e.g., non-valvular atrialfibrillation), chronic kidney disease, such as end stage renal failure(ESRD) undergoing hemodialysis. In further specific aspects, the patienthas a demonstrated high risk of bleeding. In specific aspects,non-limiting examples of anti-FXI/FXIa antibody binding agents for usein these methods include antibodies (e.g., anti-idiotype antibodies andfragments thereof such as Fabs) and antigen-binding fragments, such asFab fragments, described herein, e.g., in Table 2, for example,antibodies IDT1, IDT2, IDT3, IDT4, IDT5, IDT6, IDT7, IDT8, IDT9, andIDT10; antibodies comprising VH CDRs and VL CDRs of such antibodies;antibodies that bind the same epitope(s) within target antibody NOV1401as such antibodies.

In a particular aspect, provided herein are methods of managing bleedingor bleeding risk in a patient treated or administered an anti-FXIantibody described herein (e.g., antibody described in Table 1 such asNOV1401 or an anti-FXI antibody comprising HCDRs and LCDRs of NOV1401),comprising the step of administering to the patient in need thereof, ananti-idiotype antibody, or antigen binding fragment thereof (e.g., Fab),of the anti-FXI antibody, wherein the anti-idiotype or antigen bindingfragment thereof (e.g., Fab) specifically binds to the anti-FXI antibodyand blocks the anti-FXI antibody from binding to FXI. In specificembodiments, an anti-idiotype antibody or antigen binding fragmentthereof (e.g., Fab) reverses the effects of an anti-FXI antibodydescribed herein to mitigate bleeding risks, for example during urgentmajor surgery or trauma.

In specific aspects, an anti-idiotype antibody or antigen bindingfragment thereof (e.g., Fab) reverses or inhibits an anti-FXI antibody'santi-coagulant effects. In particular aspects, the anti-idiotypeantibody or antigen binding fragment thereof (e.g., Fab) is administeredto a patient in need thereof to temporarily reverse the anti-coagulanteffect of an anti-FXI antibody described herein (e.g., antibodydescribed in Table 1 such as NOV1401 or an anti-FXI antibody comprisingHCDRs and LCDRs of NOV1401).

In a particular aspect, provided herein are methods of managing bleedingor bleeding risk in a patient treated or administered an anti-FXIantibody such as NOV1401 (e.g., SEQ ID NOs: 14 and 25), comprising thestep of administering to the patient in need thereof, an anti-idiotypeantibody, or antigen binding fragment thereof (e.g., Fab), of theanti-FXI antibody such as NOV1401 (e.g., SEQ ID NOs: 14 and 25), whereinthe anti-idiotype, or antigen binding fragment thereof (e.g., Fab),specifically binds to the antigen-binding region of an anti-FXI antibodysuch as NOV1401 (e.g., SEQ ID NOs: 14 and 25) and blocks the anti-FXIantibody from binding to FXI and/or FXIa. In a specific embodiment, theanti-idiotype antibody, or antigen binding fragment thereof (e.g., Fab),of an anti-FXI antibody such as NOV1401 (e.g., SEQ ID NOs: 14 and 25)reverses or inhibits one or more of the anti-coagulant effects of theanti-FXI antibody (e.g., NOV1401). In certain embodiments, a temporaryreversal or inhibition of one or more of the anti-coagulant effects ofthe anti-FXI antibody (e.g., NOV1401) is achieved. In specificembodiments, following the temporary reversal or inhibition of theanti-FXI antibody (e.g., NOV1401), the anti-FXI antibody (e.g., NOV1401)is again administered to the patient.

As used herein, the terms “effective amount” or “therapeuticallyeffective amount” refer to an amount of a therapy (e.g., a binding agentprovided herein such as an anti-idiotype antibody that binds ananti-FXI/FXIa antibody (e.g., NOV1401) or a pharmaceutical compositionprovided herein) which is sufficient to reduce and/or ameliorate theseverity and/or duration of a given condition, disorder, or diseaseand/or a symptom related thereto. These terms also encompass an amountnecessary for the reduction, slowing, or amelioration of the advancementor progression of a given condition, disorder, or disease, reduction,slowing, or amelioration of the recurrence, development or onset of agiven condition, disorder or disease, and/or to improve or enhance theprophylactic or therapeutic effect(s) of another therapy (e.g., atherapy other than an anti-FXI/FXIa antibody binding agent providedherein). In some aspects, “effective amount” as used herein also refersto the amount of an antibody described herein to achieve a specifiedresult, for example, reduction or reversal in one or more anticoagulanteffects (e.g., aPTT prolongation, and reduction in the amount ofthrombin in a thrombin generation assay (TGA) in human plasma) of atarget anti-FXI/FXIa antibody; and reduction in, or blocking, binding ofa target anti-FXI/FXIa antibody to FXI/FXIa.

In specific aspects, a patient, who may be in need of, or may benefitfrom, the methods described herein (e.g., methods for reversinganticoagulant effects with anti-FXI/FXIa antibody binding agents), hasbeen treated with an anti-FXI/FXIa antibody (e.g., antibody NOV1401) tomanage, treat, prevent, or reduce the risk of a thromboembolic diseaseor disorder, e.g., thrombic stroke, atrial fibrillation, strokeprevention in atrial fibrillation (SPAF), deep vein thrombosis, venousthromboembolism, pulmonary embolism, acute coronary syndromes (ACS),ischemic stroke, acute limb ischemia, chronic thromboembolic pulmonaryhypertension, or systemic embolism. In further specific aspects, thepatient has a demonstrated high risk of bleeding.

In other aspects, a patient, who may be in need of, or may benefit from,the methods described herein (e.g., methods for reversing anticoagulanteffects with anti-FXI/FXIa antibody binding agents), has been treatedwith an anti-FXI/FXIa antibody (e.g., antibody NOV1401) for treatment ofacute VTE, primary and extended secondary prevention of VTE, preventionof major adverse thromboembolic events in patient undergoing dialysis(with or without AF), prevention of major cardiovascular and cerebralevents (MACCE) in patients with CAD undergoing PCI and receiving singleor dual antiplatelet therapy, post-acute coronary syndromes (ACS)patients, heparin induced thrombocytopenia (HIT), prevention ofthromboembolic events in heart failure patients and secondary strokeprevention.

In specific aspects, one of the following groups of subjects is beingtreated with an anti-FXI/FXIa antibody (e.g., antibody NOV1401) and maybe in need of, or benefit from, the methods described herein (e.g.,methods for reversing anticoagulant effects with anti-FXI/FXIa antibodybinding agents):

-   -   Subjects with indications for chronic anticoagulation therapy        (e.g., AF, left ventricular thrombus, prior cardioembolic        stroke)    -   subjects at intermediate-to-high risk for major bleeding;    -   subjects undergoing elective or primary percutaneous coronary        intervention (PCI) with stenting which may be require to receive        dual antiplatelet therapy (aspirin and P2Y12 receptor        antagonists) to prevent stent thrombosis.

In specific aspects, a subject, who may be in need of, or benefit from,the methods described herein (e.g., methods for reversing anticoagulanteffects with anti-FXI/FXIa antibody binding agents), has been treatedwith an anti-FXI/FXIa antibody (e.g., antibody NOV1401) to manage,treat, prevent, or reduce the risk of one of the following conditions:

-   -   thromboembolism in subjects with suspected or confirmed cardiac        arrhythmia such as paroxysmal, persistent or permanent atrial        fibrillation or atrial flutter;    -   stroke prevention in atrial fibrillation (SPAF), a subpopulation        of which is AF patients undergoing percutaneous coronary        interventions (PCI);    -   acute venous thromboembolic events (VTE) treatment and extended        secondary VTE prevention in patients at high risk for bleeding;    -   cerebral and cardiovascular events in secondary prevention after        transient ischemic attack (TIA) or non-disabling stroke and        prevention of thromboembolic events in heart failure with sinus        rhythm;    -   clot formation in left atrium and thromboembolism in subjects        undergoing cardioversion for cardiac arrhythmia;    -   thrombosis before, during and after ablation procedure for        cardiac arrhythmia;    -   venous thrombosis, this includes but not exclusively, treatment        and secondary prevention of deep or superficial veins thrombosis        in the lower members or upper member, thrombosis in the        abdominal and thoracic veins, sinus thrombosis and thrombosis of        jugular veins;    -   thrombosis on any artificial surface in the veins like catheter        or pacemaker wires;    -   pulmonary embolism in patients with or without venous        thrombosis;    -   Chronic Thromboembolic Pulmonary Hypertension (CTEPH);    -   arterial thrombosis on ruptured atherosclerotic plaque,        thrombosis on intra-arterial prosthesis or catheter and        thrombosis in apparently normal arteries, this includes but not        exclusively acute coronary syndromes, ST elevation myocardial        infarction, non ST elevation myocardial infarction, unstable        angina, stent thrombosis, thrombosis of any artificial surface        in the arterial system and thrombosis of pulmonary arteries in        subjects with or without pulmonary hypertension;    -   thrombosis and thromboembolism in patients undergoing        percutaneous coronary interventions (PCI);    -   cardioembolic and cryptogenic strokes;    -   thrombosis in patients with invasive and non-invasive cancer        malignancies;    -   thrombosis over an indwelling catheter;    -   thrombosis and thromboembolism in severely ill patients;    -   cardiac thrombosis and thromboembolism, this includes but not        exclusively cardiac thrombosis after myocardial infarction,        cardiac thrombosis related to condition such as cardiac        aneurysm, myocardial fibrosis, cardiac enlargement and        insufficiency, myocarditis and artificial surface in the heart;    -   thromboembolism in patients with valvular heart disease with or        without atrial fibrillation;    -   thromboembolism over valvular mechanic or biologic prostheses;    -   injuries or trauma in patients who had native or artificial        cardiac patches, arterial or venous conduit tubes after heart        repair of simple or complex cardiac malformations;    -   venous thrombosis and thromboembolism after knee replacement        surgery, hip replacement surgery, and orthopedic surgery,        thoracic or abdominal surgery;    -   arterial or venous thrombosis after neurosurgery including        intracranial and spinal cord interventions;    -   congenital or acquired thrombophilia including but not        exclusively factor V Leiden, prothrombin mutation, antithrombin        III, protein C and protein S deficiencies, factor XIII mutation,        familial dysfibrinogenemia, congenital deficiency of        plasminogen, increased levels of factor XI, sickle cell disease,        antiphospholipid syndrome, autoimmune disease, chronic bowel        disease, nephrotic syndrome, hemolytic uremia,        myeloproliferative disease, disseminated intra vascular        coagulation, paroxysmal nocturnal hemoglobinuria and heparin        induced thrombopenia;    -   thrombosis and thromboembolism in chronic kidney disease;    -   thrombosis and thromboembolism in end stage renal disease        (ESRD);    -   thrombosis and thromboembolism in patients with chronic kidney        disease or ESRD undergoing hemodialysis; and    -   thrombosis and thromboembolism in patients undergoing        hemodialysis and/or extra-corporal membrane oxygenation.

In a specific aspect, an anti-FXI/FXIa antibody binding agent is for usein methods of reducing bleeding or bleeding risk, or managing bleedingor bleeding risk, in a patient being treated or administered ananti-FXI/FXIa antibody (e.g., antibody NOV1401) to reduce the risk ofstroke and/or systemic embolism, wherein the patient has non-valvularatrial fibrillation.

In a specific aspect, an anti-FXI/FXIa antibody binding agent is for usein methods of reducing bleeding or bleeding risk, or managing bleedingor bleeding risk, in a patient being treated or administered ananti-FXI/FXIa antibody (e.g., antibody NOV1401) to reduce the risk ofstroke and/or systemic embolism, wherein the patient has non-valvularatrial fibrillation with a demonstrated high risk of bleeding.

In a specific aspect, an anti-FXI/FXIa antibody binding agent is for usein methods of reducing bleeding or bleeding risk, or managing bleedingor bleeding risk, in a patient being treated or administered ananti-FXI/FXIa antibody (e.g., antibody NOV1401) to reduce the risk ofstroke and/or systemic embolism, wherein the patient has ESRD and isundergoing dialysis.

In a specific aspect, an anti-FXI/FXIa antibody binding agent is for usein methods of reducing bleeding or bleeding risk, or managing bleedingor bleeding risk, in a patient being treated or administered ananti-FXI/FXIa antibody (e.g., antibody NOV1401) to reduce the risk ofstroke and/or systemic embolism, wherein the patient has non-valvularatrial fibrillation and ESRD and is undergoing dialysis.

In specific aspects, a subject, who may be in need of, or benefit from,the methods described herein (e.g., methods for reversing anticoagulanteffects with anti-FXI/FXIa antibody binding agents), has been treatedwith an anti-FXI/FXIa antibody (e.g., antibody NOV1401) in combinationwith other agents for the prevention, treatment, or improvement ofthromboembolic disorders. For example, statin therapies may be used incombination with the FXIa antibodies and antigen binding fragments ofthe present disclosure for the treatment of patients with thromboticand/or thromboembolic disorders. Such subjects undergoing combinationtherapy may be in need of, or benefit from, the methods described herein(e.g., methods for reversing anticoagulant effects with anti-FXI/FXIaantibody binding agents).

In a specific aspect, provided herein are methods of reducing bleedingor bleeding risk, or managing bleeding or bleeding risk, in a patientbeing treated or administered an anti-FXI/FXIa antibody (e.g., antibodyNOV1401), said method comprises administering a binding agent whichspecifically binds to the anti-FXI/FXIa antibody (e.g., antibodyNOV1401), and reverses an anticoagulant effect of the anti-FXI/FXIaantibody. In particular aspects, the bleeding or bleeding risk isassociated with trauma, surgery, or post-delivery. In another particularaspect, the bleeding or bleeding risk is associated with emergencysurgery or urgent procedures. In other particular aspects, the bleedingis life-threatening or uncontrolled. In specific aspects, the bindingagent is an antibody, such as an anti-idiotype antibody whichspecifically binds an anti-FXI/FXIa antibody (e.g., NOV1401). Inadditional specific aspects, the binding agent is an anti-idiotypeantibody which specifically binds to one or more epitopes within thevariable regions of an anti-FXI/FXIa antibody (e.g., NOV1401). In morespecific aspects, the binding agent is a Fab fragment of ananti-idiotype antibody which specifically binds to an anti-FXI/FXIaantibody (e.g., NOV1401). In particular aspects, the binding agent is ananti-idiotype antibody or antigen-binding fragment thereof comprisingamino acid sequences selected from Table 2. In particular aspects, thebinding agent is an anti-idiotype antibody or antigen-binding fragmentthereof, such as a Fab fragment, comprising VH and VL amino acidsequences of antibody IDT1, IDT2, IDT3, IDT4, IDT5, IDT6, IDT7, IDT8,IDT9, or IDT10, as set forth in Table 2. In particular aspects, thebinding agent is an anti-idiotype antibody or antigen-binding fragmentthereof, such as a Fab fragment, comprising VH and VL amino acidsequences of antibody IDT2, IDT3, IDT4, or IDT5, as set forth in Table2. In particular aspects, the binding agent is an anti-idiotype antibodyor antigen-binding fragment thereof, such as a Fab fragment, comprisingVH and VL amino acid sequences of antibody IDT1 or IDT3, as set forth inTable 2.

In specific aspects, bleeding is typically associated with, but notlimited to, trauma, surgery, menstruation or post-delivery. Therefore,under these circumstances, a subject, who has been treated with ananti-FXI/FXIa antibody (e.g., NOV1401), may be in need of quick andeffective therapy, such as an anti-FXI/FXIa antibody binding agentdescribed herein, to reduce bleeding or to reduce bleeding risk. Inspecific aspects, prolonged bleeding may occur after a major trauma orafter surgery, such as surgery involving organs with high fibrinolyticarea such as buccal, nasal, genital or urinary mucosa. Tooth extraction,tonsillectomy and ablation of the uterus or prostate are morenon-limiting examples of surgeries that entail a high risk of bleeding.In specific aspects, concomitant use of antiplatelets, otheranticoagulants and fibrinolytic agents can increase the risk ofbleeding.

In certain aspects, a temporary reversal or inhibition of one or more ofthe anticoagulant effects of an anti-FXI antibody (e.g., antibodyNOV1401) is desired. In a particular aspect, provided herein are methodsof reducing or managing bleeding or bleeding risk in a patient treatedor administered an anti-FXI/FXIa antibody such as antibody NOV1401,comprising the step of administering to the patient in need thereof, abinding agent described herein, such as antibody IDT1, IDT2, IDT3, IDT4,IDT5, IDT6, IDT7, IDT8, IDT9, or IDT10 or a Fab fragment thereof, onceor twice, over a period of time (e.g., 1 hour to 24 hours or to 48hours), followed by administering the anti-FXI/FXIa antibody, wherein atemporary reversal or inhibition of one or more of the anticoagulanteffects of the anti-FXI antibody is achieved.

In certain aspects, an anti-FXI/FXIa antibody binding agent describedherein can be administered in combination with another anticoagulantreversal therapy. Non-limiting examples of conventional strategies forreversing anticoagulant effects include (i) fluid replacement usingcolloids, crystalloids, human plasma or plasma proteins such as albumin;or (ii) transfusion with packed red blood or whole blood. Examples oftherapies for reversal of the effects of anticoagulants, for example, incases of severe emergency, include, but are not limited to,prohemostasis blood components such as fresh frozen plasma (FFP),prothrombin complex concentrates (PCC) and activated PCC [(APCC); e.g.factor VIII inhibitor bypass activity (FEIBA)] and recombinant activatedfactor VII (rFVIIa).

In specific aspects, the present disclosure relates to methods forreversing the anticoagulant effect of an anti-FXI/FXIa antibody (e.g.,antibody NOV1401) in a patient being treated with the anti-FXI/FXIaantibody or antigen-binding fragment thereof, comprising (i)administering to the patient an effective amount of a binding agentprovided herein, e.g., a binding agent (e.g., antibody orantigen-binding fragment thereof, such as a Fab fragment) which binds ananti-FXI/FXIa antibody and is capable of reversing one or moreanticoagulant effects; and (ii) administering to the patient anotheranticoagulant reversal therapy, such as fresh frozen plasma (FFP),prothrombin complex concentrates (PCC), activated PCC or recombinantactivated factor VII (rFVIIa). In specific aspects, the presentdisclosure relates to methods for reversing the anticoagulant effect ofan anti-FXI/FXIa antibody (e.g., antibody NOV1401) in a patient beingtreated with the anti-FXI/FXIa antibody or antigen-binding fragmentthereof, comprising (i) administering to the patient an effective amountof a binding agent provided herein, e.g., a binding agent (e.g.,antibody or antigen-binding fragment thereof, such as a Fab fragment)which binds an anti-FXI/FXIa antibody and is capable of reversing one ormore anticoagulant effects; and (ii) administering to the patient freshfrozen plasma (FFP). In specific aspects, such method achieveshomeostasis.

In certain aspects, provided herein is a method of managing bleeding ina patient being treated with an anti-FXI antibody provided herein (e.g.,an antibody described in Table 1, such as, an anti-FXI antibodycomprising VL CDRs and VHCDRs of NOV1401), said method comprisestemporarily reversing of the anticoagulant effect for a sufficient timeto manage the bleeding. In specific embodiments, the step of reversingof the anticoagulant effect comprises (i) fluid replacement usingcolloids, crystalloids, human plasma or plasma proteins such as albumin;or (ii) transfusion with packed red blood or whole blood. In specificaspects, therapeutic agents for reversal of the effect ofanticoagulants, for example, in cases of severe emergency, include, butare not limited to, prohemostasis blood components such as fresh frozenplasma (FFP), prothrombin complex concentrates (PCC) and activated PCC(APCC) (e.g. factor VIII inhibitor bypass activity (FEIBA)), andrecombinant activated factor VII (rFVIIa). In one particular aspect, aregimen may comprise administration of rFVIIa at a dose of 30 μg/kgfollowed by administration of rFVIIa at a dose of 15-30 μg/kg every 2-4hours for 24-48 hours in addition to tranexamic acid 1 g every 6 hoursfor 5 to 7 days may have potential to recover hemostasis and stopbleeding in subjects treated with an anti-FXI antibody (e.g., NOV1401 oran antibody comprising VL CDRs and VH CDRs of NOV1401) who areundergoing major surgery and in patients with an active non-accessiblebleeding site. For instance, Riddell et al reported experience in 4patients with severe FXI deficiency without inhibitor undergoing surgery(Riddell et al., 2011, Thromb. Haemost., 106: 521-527); patients wereadministered rFVIIa 30 μg/kg and tranexamic acid 1 g i.v. at inductionof anesthesia. Subsequent bolus doses of rFVIIa 15-30 μg/kg wereadministered at 2 to 4 hourly intervals as guided by rotationalthromboelastometry (ROTEM) results. In specific examples, patients weretreated with rFVIIa at above mentioned doses for 24-48 hours. Inparticular examples, tranexamic acid 1 g every six-hourly was continuedfor five days. In this small series, rFVIIa at doses as low as 15-30μg/kg in combination with tranexamic acid was safe and effective incorrecting the hemostatic defect in severe FXI deficiency in this study.In another study comprising 4 patients with severe FXI deficiency withinhibitor (autologous neutralizing FXI antibodies usually acquired aftertransfusion or administration of blood products to patients with severeFXI deficiency) who experienced 5 surgeries, the authors (Livnat et al.,2009, Thromb. Haemost.; 102: 487-492) applied the following protocol: 1g of tranexamic acid orally two hours before surgery, then patientsreceived immediately prior to the interventions another 1 g tranexamicacid i.v. Recombinant FVIIa at doses ranging from 15 to 30 μg/kg wasinfused at the completion of surgery. Subsequently, oral tranexamic acid1 g was given every 6 hour for at least 7 days. Fibrin glue was sprayedat the bed of the extirpated gallbladder in one patient. This protocolsecured normal hemostasis in patients with severe FXI deficiency withinhibitor. In one aspect, fibrin glue can be used to restore localhemostasis during dental surgery in patients with FXI deficiency(Bolton-Maggs (2000) Haemophilia; 6 (S1):100-9). In a certain embodimentwith respect to methods to manage bleeding in patients being treatedwith an anti-FXI antibody provided herein (e.g., NOV1401), a regimenconsisting of tranexamic acid 1 g every 6 hours for 5 to 7 daysassociated with the use of fibrin glue could be used to establish localhemostasis in subjects undergoing minor surgery and in subjects withaccessible bleeding site, including oral and nasal bleeding events.

In certain aspects, provided herein is a method of managing bleeding orbleeding risk in a patient being treated with an anti-FXI/FXIa antibodyprovided herein (e.g., an antibody described in Table 1, such as,NOV1401 or an anti-FXI/FXIa antibody comprising VL CDRs and VHCDRs ofNOV1401), said method comprising administering to the patient ananticoagulant reversal therapy capable of reversing (e.g., partiallyreversing) the anticoagulant effects of the anti-FXI/FXIa antibody. Inspecific aspects, the anticoagulant reversal therapy capable ofreversing the anticoagulant effect of the anti-FXI/FXIa antibody isrFVIIa (recombinant Factor VIIa), emicizumab (ACE910), tranexamic acid,Fresh Frozen Plasma (FFP), Hemoeleven, Prothrombin Complex Concentrate(PCC), Activated PCC, or FEIBA (a FVIII inhibitor complex). In specificaspects, the anticoagulant reversal therapy is administered alone, or incombination with a binding agent provided herein (e.g., binding agentdescribed in Table 2).

In specific aspects, the present disclosure relates to methods forreversing (e.g., partially reversing) the anticoagulant effect of ananti-FXI/FXIa antibody (e.g., an anti-FXI/FXIa antibody described inTable 1 such as antibody NOV1401 or an anti-FXI/FXIa antibody comprisingVH CDRs and VL CDRs of NOV1401) in a patient being treated with theanti-FXI/FXIa antibody or antigen-binding fragment thereof, comprisingadministering to the patient an anticoagulant reversal therapy, such asrFVIIa (recombinant Factor VIIa), emicizumab (ACE910), tranexamic acid,Fresh Frozen Plasma (FFP), Hemoeleven, Prothrombin Complex Concentrate(PCC), Activated PCC, or FEIBA (a FVIII inhibitor complex).

In specific aspects, the present disclosure relates to methods forreversing the anticoagulant effect of an anti-FXI/FXIa antibody (e.g.,an anti-FXI/FXIa antibody described in Table 1 such as antibody NOV1401or an anti-FXI/FXIa antibody comprising VH CDRs and VL CDRs of NOV1401)in a patient being treated with the anti-FXI/FXIa antibody orantigen-binding fragment thereof, comprising (i) administering to thepatient an effective amount of a binding agent provided herein, e.g., abinding agent (e.g., antibody or antigen-binding fragment thereof, suchas a Fab fragment) which binds an anti-FXI/FXIa antibody and is capableof reversing one or more anticoagulant effects; and (ii) administeringto the patient another anticoagulant reversal therapy, such as rFVIIa(recombinant Factor VIIa), emicizumab (ACE910), tranexamic acid, FreshFrozen Plasma (FFP), Hemoeleven, Prothrombin Complex Concentrate (PCC),Activated PCC, or FEIBA (a FVIII inhibitor complex).

In specific aspects, the risk of thromboembolic events including stroke,systemic embolism, coronary or peripheral artery thrombosis, venousthrombosis and pulmonary embolism increases with presence ofpredisposing factors such as thrombophilia, vessel wall damage andstasis. Evaluation of medical history, familiar antecedents andassociated co-morbidities can help to stratify patients according totheir thromboembolic risks. In patients with atrial fibrillation,several scoring systems e.g., CHADS2 and CHA2DS2-VASc have beendeveloped to assess stroke risk. Each was developed based on data fromrandomized trials, and clinical and epidemiologic cohort studies, andtranslated a weighted, multivariate formula of stroke risk factors to asimplified, easy-to-use mnemonic device, algorithm, calculator, oronline tool. The CHADS2 risk score was used stratification tool topredict thromboembolic risk in atrial fibrillation patients (Lip (2011)Am J Med;124(2):111-4; Camm et al (2012) Eur Heart J; 33: 2719-2747);however, accumulated evidence shows that CHA2DS2-VASc is at least asgood as or possibly better than, scores such as CHADS2 in identifyingpatients who develop stroke and thromboembolism and definitively betterat identifying ‘truly low-risk’ patients with atrial fibrillation. TheCHA2DS2-VASc score is presently recommended by Guidelines (Camm et al(2012) Eur Heart J 33, 2719-2747; January et al, AHA/ACC/HRS AtrialFibrillation Guideline; J Am Coll Cardiol 2014; 64:2246-80) to guide thedecision with regard to patients who should benefit of anticoagulanttherapy and also to identify low risk patients in whom anticoagulationtherapy is not warranted.

Bleeding risk assessment tools specific to the atrial fibrillationpatients e.g., HAS-BLED, ATRIA, HEMORR2HAGES; ORBIT and ABC risk scorewere developed to predict the bleeding risk in patients with atrialfibrillation. Unfortunately, as the bleeding risk is tightly correlatedwith the stroke risk, those risk score were of rather limited value toguide therapeutic decisions to use vitamin K antagonists such aswarfarin or NOACS. However, bleeding risk scores may become ofconsiderable help to identify patients who can benefit of a new therapywith a reduced bleeding risk e.g. anti-FXI/FXIa antibody (e.g., antibodyNOV1401).

In certain aspects, subjects with a bleeding risk, for example ademonstrated high risk of bleeding, may be identified by previousmedical history of bleeding, for example, bleeding during or aftersurgery or bleeding when treated with an anticoagulant (e.g. Warfarin).In addition, subjects with a bleeding risk, for example a demonstratedhigh risk of bleeding, may be identified by in vitro/ex vivo assaysknown in the art, for example, assays with a subject's plasma measuringaPTT and other biomarkers of the extrinsic coagulation pathways, such asprothrombin time (PT) and thrombin time (TT).

In particular aspects, subjects with moderate to high risk for strokeand systemic embolism have a CHA2DS2VASc risk score ≥2. In furtherparticular aspects, subjects with a HAS BLED risk score ≥3 ischaracterized as having a high risk of bleeding (see Gallego, et al.,(2012) Carc Arrhythm Electrophysiol.; 5:312-318, and Friberg et al.,(2012) Circulation; 125:2298-2307).

In specific aspects, a subject being treated by the methods providedherein is a human subject at least 18 years old. In another aspect, asubject being treated by the methods provided herein is a human subjectat least 50 years old. In another aspect, a subject being treated by themethods provided herein is a human subject at least 55 years old. Inanother aspect, a subject being treated by the methods provided hereinis a human subject at least 60 years old. In another aspect, a subjectbeing treated by the methods provided herein a human subject is at least65 years old.

In particular aspects, a subject being treated by the methods providedherein (e.g., methods for treating VTE or for secondary prevention ofVTE) is between the age of 2 and 18 years old. In particular aspects, asubject being treated by the methods provided herein (e.g., methods fortreating VTE or for secondary prevention of VTE) is between the age of12 and 18 years old. In particular aspects, a subject being treated bythe methods provided herein (e.g., methods for treating VTE or forsecondary prevention of VTE) is a child at least 2 years old and under18 years old. In particular aspects, a subject being treated by themethods provided herein (e.g., methods for treating VTE or for secondaryprevention of VTE) is a child at least 12 years old and under 18 yearsold.

In specific aspects, a subject (e.g., human subject) being treated bythe methods provided herein has a body mass index (BMI) that is greaterthan or equal to 18 kg/m². In another aspect, a subject being treated bythe methods provided herein has a BMI that is greater than or equal to30 kg/m². In another aspect, a subject being treated by the methodsprovided herein has a BMI that is greater than or equal to 35 kg/m². Inanother aspect, a subject being treated by the methods provided hereinhas a BMI that is greater than or equal to 40 kg/m².

In certain aspects, methods for reversing the anticoagulant effects ofan anti-FXI/FXIa antibody (e.g., antibody NOV1401) with an anti-FXI/FXIaantibody binding agent described herein, results in (i) reduction orreversal in aPTT prolongation as determined with aPTT assays with humanplasma; (ii) reduction in the amount of thrombin in a thrombingeneration assay (TGA) amount of thrombin in a thrombin generation assay(TGA) in human plasma; and/or (iii) reduction or reversal of bleeding orbleeding risk. In specific aspects, reversal of the anticoagulanteffects is less than 100%, but is sufficient to achieve a clinicallybeneficial outcome, e.g., reduction or stop in bleeding.

In certain aspects, methods for reversing the anticoagulant effect of ananti-FXI/FXIa antibody (e.g., antibody NOV1401) with an anti-FXI/FXIaantibody binding agent described herein, results in reduction orreversal in aPTT prolongation as determined with aPTT assays with humanplasma, by at least 10%, at least 20%, at least 30%, at least 40%, atleast 50%, at least 60%, at least 70%, at least 80%, or at least 90%.

Pharmaceutical Compositions

The present disclosure provides pharmaceutical compositions comprisinganti-FXI/FXIa antibody-binding agents described herein (e.g., antibodydescribed in Table 2 and Fab fragments thereof) formulated together witha pharmaceutically acceptable carrier. The compositions can additionallycontain one or more other therapeutic agents that are suitable fortreating or preventing, for example, thromboembolic disorders (e.g.,thrombotic disorders). Pharmaceutically acceptable carriers enhance orstabilize the composition, or can be used to facilitate preparation ofthe composition. Pharmaceutically acceptable carriers include solvents,dispersion media, coatings, antibacterial and antifungal agents,isotonic and absorption delaying agents, and the like that arephysiologically compatible.

A pharmaceutical composition of the present disclosure can beadministered by a variety of methods known in the art. The route and/ormode of administration vary depending upon the desired results. It ispreferred that administration be intravenous, intramuscular,intraperitoneal, or subcutaneous, or administered proximal to the siteof the target. The pharmaceutically acceptable carrier should besuitable for intravenous, intramuscular, subcutaneous, parenteral,spinal or epidermal administration (e.g., by injection or infusion).Depending on the route of administration, the active compound, i.e.,antibody, bispecific and multispecific molecule, may be coated in amaterial to protect the compound from the action of acids and othernatural conditions that may inactivate the compound.

In specific aspects, a composition should be sterile and fluid. Properfluidity can be maintained, for example, by use of coating such aslecithin, by maintenance of required particle size in the case ofdispersion and by use of surfactants. In many cases, it is preferable toinclude isotonic agents, for example, sugars, polyalcohols such asmannitol or sorbitol, and sodium chloride in the composition. Long-termabsorption of the injectable compositions can be brought about byincluding in the composition an agent which delays absorption, forexample, aluminum monostearate or gelatin.

Pharmaceutical compositions of the present disclosure can be prepared inaccordance with methods well known and routinely practiced in the art.See, e.g., Remington: The Science and Practice of Pharmacy, MackPublishing Co., 20th ed., 2000; and Sustained and Controlled ReleaseDrug Delivery Systems, J. R. Robinson, ed., Marcel Dekker, Inc., NewYork, 1978. Pharmaceutical compositions are preferably manufacturedunder GMP conditions. Typically, a therapeutically effective dose orefficacious dose of the FXIa-binding antibody is employed in thepharmaceutical compositions of the present disclosure. The FXIa-bindingantibodies are formulated into pharmaceutically acceptable dosage formsby conventional methods known to those of skill in the art. Dosageregimens are adjusted to provide the optimum desired response (e.g., atherapeutic response). For example, a single bolus may be administered,several divided doses may be administered over time or the dose may beproportionally reduced or increased as indicated by the exigencies ofthe therapeutic situation. It is especially advantageous to formulateparenteral compositions in dosage unit form for ease of administrationand uniformity of dosage. Dosage unit form as used herein refers tophysically discrete units suited as unitary dosages for the subjects tobe treated; each unit contains a predetermined quantity of activecompound calculated to produce the desired therapeutic effect inassociation with the required pharmaceutical carrier.

Actual dosage levels of the active ingredients in the pharmaceuticalcompositions of the present disclosure can be varied so as to obtain anamount of the active ingredient which is effective to achieve thedesired therapeutic response for a particular patient, composition, andmode of administration, without being toxic to the patient. The selecteddosage level depends upon a variety of pharmacokinetic factors includingthe activity of the particular compositions of the present disclosureemployed, thereof, the route of administration, the time ofadministration, the rate of excretion of the particular compound beingemployed, the duration of the treatment, other drugs, compounds and/ormaterials used in combination with the particular compositions employed,the age, sex, weight, condition, general health and prior medicalhistory of the patient being treated, and like factors.

A physician can start doses of the antibodies of the present disclosureemployed in the pharmaceutical composition at levels lower than thatrequired to achieve the desired therapeutic effect and graduallyincrease the dosage until the desired effect is achieved. In general,effective doses of the compositions of the present disclosure, for thetreatment of a thrombotic and/or thromboembolic disorders describedherein vary depending upon many different factors, including means ofadministration, target site, physiological state of the patient, othermedications administered, and whether treatment is prophylactic ortherapeutic. Treatment dosages need to be titrated to optimize safetyand efficacy. For systemic administration with an antibody, the dosageranges from about 0.01 to 15 mg/kg of the host body weight. Foradministration with an antibody, the dosage may range from 0.1 mg to 5mg. For example, 0.1 mg/kg, 0.2 mg/kg, 0.3 mg/kg, 0.4 mg/kg, 0.5 mg/kg,0.6 mg/kg, 0.7 mg/kg, 0.8 mg/kg, 0.9 mg/kg, 1.0 mg/kg, 1.1 mg/kg, 1.2mg/kg, 1.3 mg/kg, 1.4 mg/kg, 1.5 mg/kg, 1.6 mg/kg, 1.7 mg/kg, 1.8 mg/kg,1.9 mg/kg, 2.0 mg/kg, 2.1 mg/kg, 2.2 mg/kg, 2.3 mg/kg, 2.4 mg/kg, 2.5mg/kg, 2.6 mg/kg, 2.7 mg/kg, 2.8 mg/kg, 2.9 mg/kg, 3.0 mg/kg, 3.1 mg/kg,3.2 mg/kg, 3.3 mg/kg, 3.4 mg/kg, 3.5 mg/kg, 3.6 mg/kg, 3.7 mg/kg, 3.8mg/kg, 3.9 mg/kg, 4.0 mg/kg, 4.1 mg/kg, 4.2 mg/kg, 4.3 mg/kg, 4.4 mg/kg,4.5 mg/kg, 4.6 mg/kg, 4.7 mg/kg, 4.8 mg/kg, 4.9 mg/kg, or 5.0 mg/kg.

In a certain aspect, an anti-FXI/FXIa antibody binding agent describedherein is administered, for example by i.v. or s.c. route, at a dose inthe range of 5 mg to 600 mg.

In a certain aspect, an anti-FXI/FXIa antibody binding agent describedherein is administered, for example by i.v. or s.c. route, at a dose ofapproximately 5 mg, 10 mg, 15 mg, 20 mg, 30 mg, 40 mg, 50 mg, 60 mg, 90mg, 100 mg, 120 mg, 150 mg, 180 mg, 200 mg, 210 mg, 240 mg, 250 mg, 270mg, 300 mg, 330 mg, 350 mg, 360 mg, 390 mg, 400 mg, 420 mg, 450 mg, 480mg, 500 mg, 510 mg, 540 mg, 550 mg, 570 mg, or 600 mg.

In particular aspects, an antibody is usually administered on multipleoccasions. Intervals between single dosages can be weekly, biweekly,monthly or yearly. Intervals can also be irregular as indicated bymeasuring blood levels of antibody in the patient. In additionalternative dosing intervals can be determined by a physician andadministered monthly or as necessary to be efficacious. In some methodsof systemic administration, dosage is adjusted to achieve a plasmaantibody concentration of 1-1000 μg/ml and in some methods 25-500 μg/ml.Alternatively, antibody can be administered as a sustained releaseformulation, in which case less frequent administration is required.Dosage and frequency vary depending on the half-life of the antibody inthe patient. In general, humanized antibodies show longer half life thanthat of chimeric antibodies and nonhuman antibodies. The dosage andfrequency of administration can vary depending on whether the treatmentis prophylactic or therapeutic. In certain aspects for prophylacticapplications, a relatively low dosage is administered at relativelyinfrequent intervals over a long period of time. Some patients continueto receive treatment for the rest of their lives. In certain aspects fortherapeutic applications, a relatively high dosage at relatively shortintervals is sometimes required until progression of the disease isreduced or terminated, and preferably until the patient shows partial orcomplete amelioration of symptoms of disease. Thereafter, the patientcan be administered a prophylactic regime.

In specific aspects, an anti-FXI/FXIa binding agent described herein isadministered for a temporary duration or period of time when reversal ofanticoagulant effects of an anti-FXI/FXIa antibody is desired. Inspecific aspects, an anti-FXI/FXIa binding agent described herein isadministered once, few times, for a temporary duration or period of time(e.g., 1 hour to 24 hours or to 48 hours but generally not exceeding 7days) when reversal of anticoagulant effects of an anti-FXI/FXIaantibody is desired to achieve homeostasis.

EXAMPLES

The following examples are provided to further illustrate the presentdisclosure but not to limit its scope. Other variants of the presentdisclosure will be readily apparent to one of ordinary skill in the artand are encompassed by the appended claims.

Example 1 Human Fab Phage Library Panning Phage Display Panning

Antibodies against NOV1401 were generated by the selection of clonesthat bound to NOV1401 using as a source of antibody a commerciallyavailable phage display library, the Morphosys HuCAL PLATINUM library.The phagemid library is based on the HuCAL® concept (Knappik et al.,2000, J Mol Biol 296: 57-86) and employs the CysDisplay™ technology fordisplaying the Fab on the phage surface (WO01/05950). For the isolationof anti-NOV1401 antibodies a solid phase panning strategy was employedwith direct coating of NOV1401 to a Maxisorp™ (Nunc) 96 well platefollowed by three rounds of panning with increasing washing stringency.

Subcloning and Microexpression of Selected Fab Fragments

To facilitate rapid expression of soluble Fab, the Fab encoding insertsof the selected HuCAL PLATINUM® phage were subcloned from pMORPH® 30display vector into pMORPH® x11 expression vector pMORPH® x11_FH.

For initial screening and characterization an overnight cultures ofindividual Fab-expressing E. coli clones were lysed using 2× BBSsolution (400 mM Boric acid, 300 mM Sodium chloride, 5 mM EDTA)supplemented with 2.5 mg/mL lysozyme. Fab containing E. coli lysateswere used for ELISA screening.

ELISA Screening

Using ELISA screening, single Fab clones were identified from panningoutput for binding to NOV1401. Fabs were tested using Fab containingcrude E. coli lysates.

For identification of NOV1401 binding Fab fragments Maxisorp™ (Nunc) 384well plates were directly coated with 5 ug/ml NOV1401. After blocking ofplates with Superblock®, Fab-containing E. coli lysates were added.Binding of Fabs was detected by F(ab)2 specific goat anti-human IgGconjugated to alkaline phosphatase (diluted 1:5000) using Attophosfluorescence substrate (Roche, catalogue #11681982001). Fluorescenceemission at 535 nm was recorded with excitation at 430 nm.

Engineering to Remove Potential Deamidation Sites

In order to remove potential liabilities in long term storage potentialdeamidation sites (Asn-Gly or Asn-Ser) were removed by replacingasparagine to serine or glutamine. Genes including the altered aminoacids were generated via gene synthesis.

Expression and Purification of HuCAL® Fab Fragments

Expression of Fab fragments was performed in E. coli TG1 F-cells.Cultures were incubated at 37° C. until the OD600 reached a value of0.5. Fab expression was induced by addition of IPTG to a finalconcentration of 0.75 mM and cultures were further incubated o/n at 30°C. and 180 rpm. Cells were harvested and disrupted. His6-tagged Fabfragments were isolated via IMAC and gel filtration and proteinconcentrations were determined by UV-spectrophotometry at 280 nm.

Example 2 Binding Data Surface Plasmon Resonance (SPR) Binding Analysisof Anti-NOV1401 Fab Binding to NOV1401

SPR binding experiments were performed on a ProteOn XPR36 instrument(Bio-Rad Laboratories, Inc.) in PBS/T buffer (50 mM phosphate, 150 mMNaCl, pH 7.4, 0.005% v/v Tween-20) at 25° C. NOV1401 (‘Ligand’) wasimmobilized onto an activated ProteOn GLC sensor chip (Bio-RadLaboratories, Inc.) using standard amine coupling procedures asdescribed by the manufacturer. Briefly, NOV1401 was injected at aconcentration of 10 μg/ml in 20 mM sodium acetate, pH 5.0 and at a flowrate of 30 μl/min for 10 min. Unreacted groups were blocked by injecting1 M ethanolamine.

For kinetic studies anti-NOV1401 Fabs (‘Analytes’) were diluted in PBS/Tbuffer to generate a dilution series with concentrations ranging from0.125-4 nM. Fabs were injected onto surfaces with immobilized NOV1401 ata flow rate of 100 μL/min and sensorgrams were recorded for associationand dissociation times of 220 s and 1800 s, respectively. Blank surfaceswere used for background corrections. There was no need to regeneratesurfaces since the ProteOn protein interaction array system allows torun up to six binding experiments on an identical surface in parallel.

Data processing and analysis including kon, koff, and K_(D)determination were performed with the ProteOn Manager™ software version3.1.0.6. Sensorgrams were fitted by applying a Langmuir 1:1 bindingmodel (Rmax set at global) and dissociation constants were calculatedfrom kon and koff. Table 3 shows the dissociation constants for 10anti-NOV1401 Fab determined by SPR.

TABLE 3 Summary of SPR binding data Anti- Average K_(D) StDEV NOV1401[nM] [nM] n IDT1 0.44 0.02 2 IDT2 0.23 NA 1 IDT3 0.24 0.02 2 IDT4 0.310.02 2 IDT5 0.35 0.04 2 IDT6 10.08 0.13 2 IDT7 0.33 0.01 2 IDT8 2.150.15 2 IDT9 1.92 0.00 2 IDT10 5.97 0.03 2

Solution Equilibrium Titration (SET) Binding Analysis of Anti-NOV1401Fab Binding to NOV1401

14 serial (2×) dilutions of NOV1401 were prepared in sample buffer (PBSpH 7.4 containing 0.5% (w/v) BSA and 0.02% Tween 20) and a constantconcentration of the anti-NOV1401 Fab was added to each NOV1401concentration ranging from 40 pM to 240 pM. Optimal constantanti-NOV1401 Fab concentrations and optimal starting concentrations forNOV1401 dilution series were determined in pilot experiments. A startingconcentration of 10 nM NOV1401 was used for weaker binders (K_(D)˜1 nMor higher) and a starting concentration of 2 nM was used for strongerbinders (K_(D)<0.2 nM).

30 μl/well of each dilution mix was distributed in duplicates to a384-well polypropylene Eppendorf microplate (MTP). Sample buffer servedas negative control and a sample containing no antigen as positivecontrol (Bmax). The plate was sealed and incubated overnight at RT on aplate shaker. A streptavidin (SA) plate from Pierce® (pre-blockedStreptavidin High Binding Capacity 384-Well Plate, #15505) was coated byadding 30 μl/well of 0.5 μg/ml biotinylated NOV1401 diluted in PBS,sealed and incubated for 2 h at RT on a MTP shaker.

After incubation and three times washing with PBST (PBS containing 0.05%Tween 20) 30 μl/well of the NOV1401/anti-NOV1401 Fab preparation wastransferred from the polypropylene MTP to the NOV1401-coated SA plateand incubated for 30 min at RT on a MTP shaker. After three additionalwash steps, 30 μl of 0.5 μg/ml detection antibody (Goat anti-human KappaLC-HRP, BETHYL#A80-115P) diluted in sample buffer was added to each welland incubated for 1 h at RT with shaking. After washing the plate againthree times, 30 μl of detection reagent (LumiGLO PeroxidaseChemiluminescent Substrate, KPL#54-61-01) was added to each well.Electrochemiluminescence (ECL) signals were generated and detectedimmediately with a luminescence imager (SpectraMax M5, MolecularDevices, LLC).

Average ECL-signals were calculated from duplicate measurements withineach assay. Data were baseline adjusted by subtracting the lowest valuefrom all data points and plotted against the corresponding antigenconcentration. K_(D) values were determined by fitting the plot with thefollowing non-linear curve fitting model for 1:1 binding according toHaenel et al 2005:

$y = {B_{\max} - \left( {\frac{B_{\max}}{2\lbrack{Fab}\rbrack}\left( {\lbrack{Fab}\rbrack + x + K_{D} - \sqrt{\left( {\lbrack{Fab}\rbrack + x + K_{D}} \right)^{2} - {4{x\lbrack{Fab}\rbrack}}}} \right)} \right)}$

where y is the blank-subtracted ECL signal, [Fab] is the applied Fabconcentration, x is the applied total soluble antigen (here NOV1401),Bmax is the blank-subtracted ECL signal for x=0, and K_(D) is thedissociation constant.

The SET results for nine anti-NOV1401 Fabs are summarized in Table 4 andrepresentative binding response curves are shown in FIG. 1. SET datacould not be fit for IDT6 and have not been included.

TABLE 4 Summary of SET results for anti-NOV1401 antibodies AntidoteAverage K_(D) (nM) Stdev n IDT1 0.11 0.01 2 IDT2 0.10 0.003 3 IDT3 0.100.01 2 IDT4 0.97 0.04 2 IDT5 0.14 0.02 3 IDT7 0.96 0.01 2 IDT8 0.16 0.023 IDT9 0.68 0.05 2 IDT10 1.19 0.09 2

Example 3 SPR Binding Competition

SPR experiments were performed in principle as described in Example 2with the following changes. Human plasma-derived FXIa was used as ligandand immobilized on an activated ProteOn GLC sensor chip (Bio-RadLaboratories, Inc.) using standard amine coupling procedures asdescribed and by injecting FXIa at a concentration of 10 μg/ml in 20 mMsodium acetate, pH 5.0 and at a flow rate of 30 μl/min for 10 min.

For binding competition studies NOV1401 and three mixture of NOV1401with anti-NOV1401 Fab at molar ratios of 1:1, 1:2, and 1:10 wereprepared in PBS/T buffer and injected in simultaneously onto surfaceswith immobilized FXI at a flow rate of 100 μL/min. Sensorgrams wererecorded for association and dissociation times of 220 s and 1800 s,respectively. Blank surfaces were used for background corrections.

NOV1401/anti-NOV1401 Fab mixtures yielded significantly lower bindingresponses to immobilized FXIa than NOV1401 alone with a 1/10 mixture(NOV1401/anti-NOV1401 Fab) showing no binding to FXIa. As the responseunits (RUs) in SPR are directly proportional to the mass bound to thechip, increasing concentrations of anti-NOV1401 Fab seems to preventNOV1401 from binding to FXIa indicating that anti-NOV1401 can bind toNOV1401 and block NOV1401 from binding to FXIa.

FIG. 2 shows two representative examples for anti-NOV1401 Fabs (IDT1,IDT3). Anti-NOV1401 Fabs clearly reduce NOV1401 binding to its antigenFXIa, therefore compete with FXIa for binding to NOV1401. Added to aNOV1401 solution at 10× molar excess (5× molar excess per NOV1401binding sites), anti-NOV1401 Fab completely prevents NOV1401 frombinding to FXIa, indicating that anti-NOV1401 Fabs are capable ofneutralizing free NOV1401 in solution.

Example 4 Reversal of the Anticoagulant Activity of NOV1401

Effects of anti-NOV1401 Fabs on the anticoagulant activity of NOV1401was tested by using the activated partial thromboplastin time (aPTT)assay and the thrombin generation assay (TGA).

aPTT Assay:

Lyophilized normal human plasma ‘Coagulation Control N’ (Cat #5020050)was purchased from Technoclone GmbH (Vienna, Austria). It was pooledfrom citrated plasma of selected healthy donors. The clotting timeobtained with this normal plasma reflects normal concentrations of thecoagulation factors involved in clotting. The lyophilized plasma wasstored at 4° C. Prior to its use, the plasma was re-suspended in 1 mL ofdistilled water by carefully rotating the vial and then keeping it for10 minutes at room temperature.

The intrinsic pathway triggering Dapttin TC (Cat #5035090) was purchasedfrom Technoclone GmbH (Vienna, Austria), containing phospholipid,sulfatide, and silicate. The lyophilized trigger was reconstituted indistilled water with the volume indicated on the vial.

Calcium Chloride (Fluka, Cat #21115) was prepared in distillated waterat a stock concentration of 25 mM. Phosphate Buffered Saline (PBS, LifeTechnologies, Cat #10010-023) was used as antibody dilution buffer.

The measurements of the clotting time were performed in a ballcoagulometer model MC10 (Merlin medical, Germany), which is asemi-automated mechanical clot detection system. The system utilizes aspecial cuvette in which a stainless steel ball is distributed (Merlinmedical, Cat #Z05100).

The cuvette is placed into the measuring well of the ball coagulometer.After the sample, plasma, and trigger are added to the cuvette, themeasuring well rotates slowly causing the cuvette to rotate along itslongitudinal axis. Because the cuvette is positioned at a slight angle,gravity and inertia always position the ball at the lowest point of thecuvette. Exactly opposite the ball-position is a magnetic sensor. Afteran appropriate incubation period, a timer is started with the additionof the calcium chloride solution. As coagulation takes place, fibrinstrands form in the reaction mixture. The fibrin strands pull the ballaway from its inertia position that triggers an impulse in the magneticsensor. This impulse electronically stops the timer.

Serial dilutions of NOV1401 were prepared in PBS. The reconstitutedhuman blood plasma, trigger reagent (Dapttin), calcium chloride werewarmed up in a water bath at 37° C. for 10 minutes.

The assay was performed exclusively in specialized cuvettes containing astainless steel ball. The pipetting scheme is outlined in Table 5.

TABLE 5 Pipetting scheme for measuring NOV1401 activity in aPTT assayAssay aPTT assay step Solution Volume [μL] 1 antibody dilution ordiluent 50 2 human blood plasma 50 3 Dapttin 50 4 Incubate 3 minutes at37° C. under rotation 5 25 mM Calcium Chloride 50 6 Immediately startthe timer 7 The timer stops when the clot is formed

The samples were measured in duplicates at a temperature of 37° C. inthe Merlin ball coagulometer described above.

The clot formation was timed for each concentration of NOV1401 andplotted versus the corresponding antibody concentrations. The resultingdose-response curve was fitted using the non-linear regression programGraphPad Prism (GraphPad Software Inc., La Jolla, Calif., USA). Fromfitting the dose response curve the NOV1401 concentration for doublingof the initial clotting time (sample containing plasma withoutantibody), also described as ‘2× aPTT’, was determined.

Anti-NOV1401 Fabs Block the Anticoagulant Activity of NOV1401:

To determine if anti-NOV1401 Fabs can block NOV1401's ability to prolongclotting times in the aPTT assay, several NOV1401/anti-NOV1401 Fabmixtures in PBS were generated where the NOV1401 concentration was keptconstant at a value required for 2× aPTT which was determined in aseparate experiment as described above. Anti-NOV1401 Fab was added atequimolar amount (1/1) or at molar excess, typically 1/3 or 1/5, and1/10 (n/n). The pipetting scheme is shown in Table 6.

TABLE 6 Pipetting scheme for measuring the effect of anti- NOV1401 Fabon NOV1401 activity in the aPTT assay. Assay aPTT assay step SolutionVolume [μL] 1 NOV1401 or diluent 25 2 Antidote or control Ig 25 3Incubate 10 minutes 4 Human blood plasma 50 5 Dapttin 50 6 Incubate 3minutes at 37° C. under rotation 7 25 mM Calcium Chloride 50 8Immediately start the timer 9 The timer stops when the clot is formed

The samples were measured in duplicates at a temperature of 37° C. inthe Merlin ball coagulometer described above.

The results for two anti-NOV1401 Fabs—IDT1 and IDT3—are shown in FIG. 3.At a constant NOV1401 concentration of 0.096 μM increasing amounts ofNOV1401 Fab block the effect of NOV1401 on coagulation as measured inthe aPTT assay. A three times molar excess of IDT1 or IDT3 (1.5× molarexcess per binding site) was sufficient to completely inhibit the effectof NOV1401 on aPTT.

These data confirm and extend the results from SPR competitionexperiments as they suggest that anti-NOV1401 Fabs block the function ofNOV1401 when pre-mixed with NOV1401. Together these results suggest thatanti-NOV1401 Fabs are capable to prevent free NOV1401 from binding toFXI and blocking the effects of FXI.

Anti-NOV1401 Fabs Partially Reverse the Anticoagulant Activity ofNOV1401:

To determine if anti-NOV1401 Fabs can reverse NOV1401's ability toprolong clotting times in the aPTT, NOV1401 was preincubated withFXI-containing human plasma for 5 min before anti-NOV1401 Fab was added.As in the blocking experiment the concentration of NOV1401 was keptconstant a value required for 2× aPTT determined separately in a doseresponse experiment as described above.

Anti-NOV1401 Fab was added at equimolar amount (1/1) or at molar excess,typically 1/3 and 1/10 (n/n). The pipetting scheme is shown in Table 7.

TABLE 7 Pipetting scheme for measuring reversal of the effects ofNOV1401 on aPTT by anti-NOV1401 Fab. Assay aPTT assay step SolutionVolume [μL] 1 Human blood plasma 50 2 NOV1401 or diluent 25 3 Incubate 5minutes 4 Antidote or control Ig 25 5 Incubate 10 minutes 6 Dapttin 50 7Incubate 3 minutes at 37° C. under rotation 8 25 mM Calcium Chloride 509 Immediately start the timer 10  The timer stops when the clot isformed

The samples were measured in duplicates at a temperature of 37° C. inthe Merlin ball coagulometer described above. The reversal percentage ofNOV1401 clotting time was determined for each anti-NOV1401 Fab using thefollowing equation:

Percentage reversal=(NOV1401 clotting time−antidote clottingtime)/(NOV1401 clotting time−initial clotting time)*100.

The results for all 10 anti-NOV1401 Fabs are shown in FIG. 4. At aconstant NOV1401 concentration of 0.096 μM increasing amounts ofanti-NOV1401 Fab added after NOV1401 was incubated with FXI containinghuman plasma partially reverse the effect of NOV1401 on coagulation asmeasured in the aPTT assay. While all anti-NOV1401 show some reversal,the degree of reversal at a given concentration varies and a maximumreversal of 55-65% was observed at 10× molar excess. The reversalpercentages for all anti-NOV1401 Fabs are summarized in Table 8. Theseresults suggest that anti-NOV1401 Fabs are capable of reversing, atleast partially reversing, the anticoagulant effects of NOV1401 asmeasured in the aPTT assay.

TABLE 8 Summary of aPTT reversal data for anti-NOV1401 antibodies anti-NOV1401 NOV1401/anti NOV1401 ratio (n/n) Fab 1/10 1/3 1/1 IDT1 64% 45%12 IDT2 55% 42% 21 IDT3 58% 35% 9 IDT4 39% 27% 10 IDT5 56% 42% 17 IDT638% 22% 9 IDT7 54% 37% 16 IDT8 42% 25% 8 IDT9 46% 25% 10 IDT10 40% 25%12

Thrombin Generation Assay:

To confirm the reversal of NOV1401 anticoagulant activity observed inthe aPTT assay in another functional assay, the TGA was employed tomeasure thrombin generated through the thrombin feedback loop, whichdepends on the activity of FXIa.

For the TGA lyophilized normal human plasma (Coagulation control N) waspurchased from Technoclone GmbH (Cat #5020040) and reconstituted indistilled water in a volume suggested by the manufacturer.

The substrate solution was prepared using the fluorogenic substrateZ-Gly-Gly-Arg-AMC from Technoclone GmbH (Cat #5006230). Aliquots of thelyophilized substrate were kept at 4° C. The substrate was dissolvedfreshly in the volume of distilled water indicated on the vial 20minutes prior its use in the assay. The reconstituted substrate solutioncontains the fluorogenic peptide at a concentration of 1 mM and CaCl2 ata concentration of 15 mM.

The trigger reagent ‘platelet poor plasma (PPP)-reagent low’ waspurchased from Thrombinoscope (Cat #TS31.00) and reconstituted indistilled water as indicated on the vial. ‘PPP-reagent low’ contains amixture of phospholipids and tissue factor at very low concentration.The reagent was 8-fold diluted in 80 mM Tris/HCl at pH7.4, 0.05% (w/v)CHAPS immediately before use.

The samples were aliquoted and measured in 96 well black/clear bottomplates purchased from Costar (product no 3603). For automation transfersamples were placed in V-bottom 96 well plate (Costar, 3894) andtransferred using a CyBio automation system (Analytik Jena US, Woburn,Mass, USA).

The reconstituted human blood plasma, trigger reagent ‘PPP-reagent low’and substrate were pre-warmed for 10 minutes in a water bath at 37° C.Serial 1:3 antibody dilutions in PBS were prepared in a 96 well platestarting with a NOV1401 concentration of 5 (5× the highest finalconcentration of 1 μM) for a total of 8 dilutions. 222 μl of triggerreagent was mixed with 1108 μl of substrate solution to generate the10+50 trigger reagent substrate mix. 80 μl per well was added into aV-bottom 96 well plate for later transfer using an automation system.The plate was kept at 37° C. The reagents were added according to thescheme given in Table 9.

TABLE 9 Pipetting scheme for TGA with NOV1401 Assay step Solution Volume[ul] 1 Antibody solutions (8 dilutions) 20 2 Plasma stock solution 20 5minutes incubation at 37° C. in a thermomixer at 300 rpm. 3 Triggerreagent/substrate mixture 10 + 50

Trigger/substrate mixtures were transferred using automation. Afteradding the mixtures, excitation and emission at 360 nm at 460 nm,respectively, were recorded immediately using a Synergy Neo instrument(BioTek Instrument Inc., Winooski, Vt., USA). The samples were measuredin duplicates at a temperature of 37° C. in the plate reader for 90minutes at intervals of 55 seconds.

To generate peak thrombin concentration values data were processed usingthe TGA evaluation software file provided by Technoclone. To generateplots for peak thrombin concentration vs antibody concentration datawere fit using GraphPad software. These data were fit to a non-linearregression model in the GraphPad Prism5 software (GraphPad SoftwareInc., La Jolla, Calif., USA). The IC50 value was determined using thebuilt-in four-parameter dose-response curve equation (variable slope):y=Bottom+(Top−Bottom)/(1+10{circumflex over ( )}((LogIC50-x)*Hillslope)) where y is the maximal concentration of thrombinformed at the inhibitor concentration, x, and top and bottom representthe concentration of thrombin without inhibitor and at the highestconcentration of inhibitor, respectively.

NOV1401 dose-dependently reduces thrombin in the TGA and the IC₅₀ valuedetermined by this method was used as the concentration of NOV1401 inreversal experiments with anti-NOV1401 Fabs.

Anti-NOV1401 Fab Partially Reverses the Effect of NOV1401 on ThrombinGeneration in the TGA:

To determine if anti-NOV1401 Fabs can reverse NOV1401's ability toreduce thrombin generation in the TGA, NOV1401 was preincubated withFXI-containing human plasma for 5 min before anti-NOV1401 Fab was added.The concentration of NOV1401 was kept constant at the IC₅₀ valuedetermined separately in a dose response experiment as described above.Anti-NOV1401 Fab was added at equimolar amount (1/1) or at molar excess,typically 1/3 and 1/10 (n/n). The pipetting scheme is shown in Table 10.

TABLE 10 Pipetting scheme for measuring the reversal of the effects ofNOV1401 on TGA by anti-NOV1401 Fab. Assay step Solution Volume [uL] 1NOV1401 solution or PBS 10 2 Antidote or control lgG 10 10 minutesincubation at 37° C. 3 Plasma stock solution 20 5 minutes incubation at37° C. in a thermomixer at 300 rpm. 4 Trigger reagent/substrate mixture10 50

The maximum concentrations of thrombin generated for each assayconditions are plotted and the percentage reversal was determined usingthe following equation:

y=(A−B)/(C−B)*100.

where y is the percentage reversal, A the thrombin concentration forassay conditions with anti-NOV1401, B is the thrombin concentration forassay conditions without anti-NOV1401, C is the initial thrombinconcentration.

The results for all 10 anti-NOV1401 Fabs are shown in FIG. 5. At aconstant NOV1401 concentration of 0.05 μM increasing amounts ofanti-NOV1401 Fab added after NOV1401 was incubated with FXI-containinghuman plasma led to an increase in thrombin concentration, hencereversing (e.g., at least partially reversing) the effect of NOV1401 onthrombin generation in the TGA. While all anti-NOV1401 show somereversal, the degree of reversal at a given concentration varies and amaximum reversal of 37-72% was observed at 10× molar excess. Thereversal percentages for all anti-NOV1401 Fabs are summarized in Table11. These results suggest that anti-NOV1401 Fabs can reverse (e.g., atleast partially reverse) the reduction of thrombin by NOV1401 in theTGA.

TABLE 11 Summary of TGA reversal data for anti-NOV1401 antibodies anti-NOV1401 NOV1401/anti NOV1401 ratio (n/n) Fab 1/10 1/3 1/1 IDT1 55% 55%49% IDT2 61% 57% 55% IDT3 67% 47% 31% IDT4 60% 53% 33% IDT5 72% 56% 55%IDT6 37% 41% 18% IDT7 71% 66% 50% IDT8 69% 56% 41% IDT9 72% 61% 41%IDT10 57% 45% 37%

Anti-NOV1401 Fabs Acutely Reverses the Anticoagulant Effects of NOV1401in Cynomolgus Monkeys:

To test if an anti-NOV1401 Fab can reverse NOV1401's ability to prolongclotting times in vivo we administered a single 3 mg/kg subcutaneousdose of NOV1401 to cynomolgus monkeys on study day one followed by twoi.v. doses of IDT3 on study day 4 and 5, respectively. A dose of 3 mg/kgs.c. was chosen for NOV1401 since it has been demonstrated that thisdose leads to sustained aPTT prolongation in cynomolgus monkeys. Basedon our in vitro experiments with human plasma, anti-NOV1401 Fab wasadministered in molar excess, for example, IDT3 was administered i.v. at10 mg/kg followed by 30 mg/kg in one animal and at 30 mg/kg followed by90 mg/kg in a second animal. Additional animals (N=2) were alsoadministered NOV1401 only (one dose of 3 mg/kg s.c. on study day one),or IDT3 only (two i.v. doses of 30 mg/kg and 90 mg/kg on study day 4 and5, respectively).

For ex-vivo aPTT analysis, blood samples were collected into sodiumcitrate coagulation tubes on study day 3, and 30 min, 2 hours, 8 hoursand 12 hours post IDT3 dose on study days 4 and 5. Additional sampleswere collected on study days 6, 7, 8, and 9. All blood samples werecentrifuged; plasma samples were obtained and frozen at approximately−70° C. or below.

In animals treated with NOV1401 alone, a single subcutaneous dose of 3mg/kg prolonged aPTT by 1.7 to 1.8× throughout the end of the studydemonstrating that NOV1401 has potent anticoagulant effects incynomolgus monkeys and confirming earlier studies.

In animals that were dosed at 10 mg/kg i.v. with IDT3 three days afterNOV1401, aPTT was normalized immediately and had reached baseline levelsat the earliest time point of 30 min after dosing (FIG. 6). After 8-12hours, the aPTT prolongating effect of NOV1401 had returned close tomaximum levels, but was reduced again to baseline after a second dose of30 mg/kg was administered. Very similar effects were observed when IDT3was dosed at 30 mg/kg and 90 mg/kg. The higher doses seem to extend thereversal effect. No effect on aPTT was observed in animals that wereonly administered IDT3 at 30 mg/kg and 90 mg/kg (FIG. 6).

These data suggest that anti-NOV1401 Fabs such as IDT3 are able toacutely reverse the effects of MAA868 on aPTT in vivo and anti-NOV1401Fabs provided herein such as IDT3 can serve as an effective reversalagent for anti-FXI/FXIa antibody NOV1401, for example in cases whenquick neutralization of anti-FXI/FXIa antibody NOV1401 be needed. Thesedata also indicate that the acute reversal observed in vivo in thismonkey study correlates with the partial reversal observed in the invitro experiments with human plasma, such as the aPTT assays describedherein.

INCORPORATION BY REFERENCE

All references cited herein, including patents, patent applications,papers, publications, text books, and the like, and the references citedtherein, to the extent that they are not already, are herebyincorporated herein by reference in their entirety.

Equivalents

The foregoing written specification is considered to be sufficient toenable one skilled in the art to practice the present disclosure. Theforegoing description and examples detail certain preferred embodimentsof the present disclosure and describe the best mode contemplated by theinventors. It will be appreciated, however, that no matter how detailedthe foregoing may appear in text, the present disclosure may bepracticed in many ways and the present disclosure should be construed inaccordance with the appended claims and any equivalents thereof.

1-30. (canceled)
 31. A polynucleotide encoding a binding agent whichspecifically binds a target antibody that binds human Factor XI (FXI)and/or Factor XIa (FXIa) within the catalytic domain, wherein the targetantibody comprises (i) a heavy chain variable region (VH) comprisingcomplementarity determining regions HCDR1, HCDR2 and HCDR3 of a VHcomprising the amino acid sequence of SEQ ID NO: 12 and (ii) a lightchain variable region (VL) comprising complementarity determiningregions LCDR1, LCDR2, and LCDR3 of a VL comprising the amino acidsequence of SEQ ID NO: 23, and wherein the binding agent is an antibodyor antigen-binding fragment thereof comprising a VH comprising HCDR1,HCDR2, and HCDR3 and a VL comprising LCDR1, LCDR2, and LCDR3, wherein:a) i) the HCDR1 comprises the amino acid sequence of SEQ ID NO: 91, theHCDR2 comprises the amino acid sequence of SEQ ID NO: 92, the HCDR3comprises the amino acid sequence of SEQ ID NO: 93, the LCDR1 comprisesthe amino acid sequence of SEQ ID NO: 107, the LCDR2 comprises the aminoacid sequence of SEQ ID NO: 108, and the LCDR3 comprises the amino acidsequence of SEQ ID NO: 109; ii) the HCDR1 comprises the amino acidsequence of SEQ ID NO: 94, the HCDR2 comprises the amino acid sequenceof SEQ ID NO: 95, the HCDR3 comprises the amino acid sequence of SEQ IDNO: 96, the LCDR1 comprises the amino acid sequence of SEQ ID NO: 110,the LCDR2 comprises the amino acid sequence of SEQ ID NO: 111, and theLCDR3 comprises the amino acid sequence of SEQ ID NO: 112; iii) theHCDR1 comprises the amino acid sequence of SEQ ID NO: 97, the HCDR2comprises the amino acid sequence of SEQ ID NO: 98, the HCDR3 comprisesthe amino acid sequence of SEQ ID NO: 99, the LCDR1 comprises the aminoacid sequence of SEQ ID NO: 113, the LCDR2 comprises the amino acidsequence of SEQ ID NO: 114, and the LCDR3 comprises the amino acidsequence of SEQ ID NO: 115; or iv) the HCDR1 comprises the amino acidsequence of SEQ ID NO: 100, the HCDR2 comprises the amino acid sequenceof SEQ ID NO: 101, the HCDR3 comprises the amino acid sequence of SEQ IDNO: 102, the LCDR1 comprises the amino acid sequence of SEQ ID NO: 116,the LCDR2 comprises the amino acid sequence of SEQ ID NO: 117, and theLCDR3 comprises the amino acid sequence of SEQ ID NO: 118; b) i) theHCDR1 comprises the amino acid sequence of SEQ ID NO: 27, the HCDR2comprises the amino acid sequence of SEQ ID NO: 28, the HCDR3 comprisesthe amino acid sequence of SEQ ID NO: 29, the LCDR1 comprises the aminoacid sequence of SEQ ID NO: 43, the LCDR2 comprises the amino acidsequence of SEQ ID NO: 44, and the LCDR3 comprises the amino acidsequence of SEQ ID NO: 45; ii) the HCDR1 comprises the amino acidsequence of SEQ ID NO: 30, the HCDR2 comprises the amino acid sequenceof SEQ ID NO: 31, the HCDR3 comprises the amino acid sequence of SEQ IDNO: 32, the LCDR1 comprises the amino acid sequence of SEQ ID NO: 46,the LCDR2 comprises the amino acid sequence of SEQ ID NO: 47, and theLCDR3 comprises the amino acid sequence of SEQ ID NO: 48; iii) the HCDR1comprises the amino acid sequence of SEQ ID NO: 33, the HCDR2 comprisesthe amino acid sequence of SEQ ID NO: 34, the HCDR3 comprises the aminoacid sequence of SEQ ID NO: 35, the LCDR1 comprises the amino acidsequence of SEQ ID NO: 49, the LCDR2 comprises the amino acid sequenceof SEQ ID NO: 50, and the LCDR3 comprises the amino acid sequence of SEQID NO: 51; or iv) the HCDR1 comprises the amino acid sequence of SEQ IDNO: 36, the HCDR2 comprises the amino acid sequence of SEQ ID NO: 37,the HCDR3 comprises the amino acid sequence of SEQ ID NO: 38, the LCDR1comprises the amino acid sequence of SEQ ID NO: 52, the LCDR2 comprisesthe amino acid sequence of SEQ ID NO: 53, and the LCDR3 comprises theamino acid sequence of SEQ ID NO: 54; c) i) the HCDR1 comprises theamino acid sequence of SEQ ID NO: 59, the HCDR2 comprises the amino acidsequence of SEQ ID NO: 60, the HCDR3 comprises the amino acid sequenceof SEQ ID NO: 61, the LCDR1 comprises the amino acid sequence of SEQ IDNO: 75, the LCDR2 comprises the amino acid sequence of SEQ ID NO: 76,and the LCDR3 comprises the amino acid sequence of SEQ ID NO: 77; ii)the HCDR1 comprises the amino acid sequence of SEQ ID NO: 62, the HCDR2comprises the amino acid sequence of SEQ ID NO: 63, the HCDR3 comprisesthe amino acid sequence of SEQ ID NO: 64, the LCDR1 comprises the aminoacid sequence of SEQ ID NO: 78, the LCDR2 comprises the amino acidsequence of SEQ ID NO: 79, and the LCDR3 comprises the amino acidsequence of SEQ ID NO: 80; iii) the HCDR1 comprises the amino acidsequence of SEQ ID NO: 65, the HCDR2 comprises the amino acid sequenceof SEQ ID NO: 66, the HCDR3 comprises the amino acid sequence of SEQ IDNO: 67, the LCDR1 comprises the amino acid sequence of SEQ ID NO: 81,the LCDR2 comprises the amino acid sequence of SEQ ID NO: 82, and theLCDR3 comprises the amino acid sequence of SEQ ID NO: 83; or iv) theHCDR1 comprises the amino acid sequence of SEQ ID NO: 68, the HCDR2comprises the amino acid sequence of SEQ ID NO: 69, the HCDR3 comprisesthe amino acid sequence of SEQ ID NO: 70, the LCDR1 comprises the aminoacid sequence of SEQ ID NO: 84, the LCDR2 comprises the amino acidsequence of SEQ ID NO: 85, and the LCDR3 comprises the amino acidsequence of SEQ ID NO: 86; d) i) the HCDR1 comprises the amino acidsequence of SEQ ID NO: 123, the HCDR2 comprises the amino acid sequenceof SEQ ID NO: 124, the HCDR3 comprises the amino acid sequence of SEQ IDNO: 125, the LCDR1 comprises the amino acid sequence of SEQ ID NO: 139,the LCDR2 comprises the amino acid sequence of SEQ ID NO: 140, and theLCDR3 comprises the amino acid sequence of SEQ ID NO: 141; ii) the HCDR1comprises the amino acid sequence of SEQ ID NO: 126, the HCDR2 comprisesthe amino acid sequence of SEQ ID NO: 127, the HCDR3 comprises the aminoacid sequence of SEQ ID NO: 128, the LCDR1 comprises the amino acidsequence of SEQ ID NO: 142, the LCDR2 comprises the amino acid sequenceof SEQ ID NO: 143, and the LCDR3 comprises the amino acid sequence ofSEQ ID NO: 144; iii) the HCDR1 comprises the amino acid sequence of SEQID NO: 129, the HCDR2 comprises the amino acid sequence of SEQ ID NO:130, the HCDR3 comprises the amino acid sequence of SEQ ID NO: 131, theLCDR1 comprises the amino acid sequence of SEQ ID NO: 145, the LCDR2comprises the amino acid sequence of SEQ ID NO: 146, and the LCDR3comprises the amino acid sequence of SEQ ID NO: 147; or iv) the HCDR1comprises the amino acid sequence of SEQ ID NO: 132, the HCDR2 comprisesthe amino acid sequence of SEQ ID NO: 133, the HCDR3 comprises the aminoacid sequence of SEQ ID NO: 134, the LCDR1 comprises the amino acidsequence of SEQ ID NO: 148, the LCDR2 comprises the amino acid sequenceof SEQ ID NO: 149, and the LCDR3 comprises the amino acid sequence ofSEQ ID NO: 150; e) i) the HCDR1 comprises the amino acid sequence of SEQID NO: 155, the HCDR2 comprises the amino acid sequence of SEQ ID NO:156, the HCDR3 comprises the amino acid sequence of SEQ ID NO: 157, theLCDR1 comprises the amino acid sequence of SEQ ID NO: 171, the LCDR2comprises the amino acid sequence of SEQ ID NO: 172, and the LCDR3comprises the amino acid sequence of SEQ ID NO: 173; ii) the HCDR1comprises the amino acid sequence of SEQ ID NO: 158, the HCDR2 comprisesthe amino acid sequence of SEQ ID NO: 159, the HCDR3 comprises the aminoacid sequence of SEQ ID NO: 160, the LCDR1 comprises the amino acidsequence of SEQ ID NO: 174, the LCDR2 comprises the amino acid sequenceof SEQ ID NO: 175, and the LCDR3 comprises the amino acid sequence ofSEQ ID NO: 176; iii) the HCDR1 comprises the amino acid sequence of SEQID NO: 161, the HCDR2 comprises the amino acid sequence of SEQ ID NO:162, the HCDR3 comprises the amino acid sequence of SEQ ID NO: 163, theLCDR1 comprises the amino acid sequence of SEQ ID NO: 177, the LCDR2comprises the amino acid sequence of SEQ ID NO: 178, and the LCDR3comprises the amino acid sequence of SEQ ID NO: 179; or iv) the HCDR1comprises the amino acid sequence of SEQ ID NO: 164, the HCDR2 comprisesthe amino acid sequence of SEQ ID NO: 165, the HCDR3 comprises the aminoacid sequence of SEQ ID NO: 166, the LCDR1 comprises the amino acidsequence of SEQ ID NO: 180, the LCDR2 comprises the amino acid sequenceof SEQ ID NO: 181, and the LCDR3 comprises the amino acid sequence ofSEQ ID NO: 182; f) i) the HCDR1 comprises the amino acid sequence of SEQID NO: 187, the HCDR2 comprises the amino acid sequence of SEQ ID NO:188, the HCDR3 comprises the amino acid sequence of SEQ ID NO: 189, theLCDR1 comprises the amino acid sequence of SEQ ID NO: 203, the LCDR2comprises the amino acid sequence of SEQ ID NO: 204, and the LCDR3comprises the amino acid sequence of SEQ ID NO: 205; ii) the HCDR1comprises the amino acid sequence of SEQ ID NO: 190, the HCDR2 comprisesthe amino acid sequence of SEQ ID NO: 191, the HCDR3 comprises the aminoacid sequence of SEQ ID NO: 192, the LCDR1 comprises the amino acidsequence of SEQ ID NO: 206, the LCDR2 comprises the amino acid sequenceof SEQ ID NO: 207, and the LCDR3 comprises the amino acid sequence ofSEQ ID NO: 208; iii) the HCDR1 comprises the amino acid sequence of SEQID NO: 193, the HCDR2 comprises the amino acid sequence of SEQ ID NO:194, the HCDR3 comprises the amino acid sequence of SEQ ID NO: 195, theLCDR1 comprises the amino acid sequence of SEQ ID NO: 209, the LCDR2comprises the amino acid sequence of SEQ ID NO: 210, and the LCDR3comprises the amino acid sequence of SEQ ID NO: 211; or iv) the HCDR1comprises the amino acid sequence of SEQ ID NO: 196, the HCDR2 comprisesthe amino acid sequence of SEQ ID NO: 197, the HCDR3 comprises the aminoacid sequence of SEQ ID NO: 198, the LCDR1 comprises the amino acidsequence of SEQ ID NO: 212, the LCDR2 comprises the amino acid sequenceof SEQ ID NO: 213, and the LCDR3 comprises the amino acid sequence ofSEQ ID NO: 214; p) i) the HCDR1 comprises the amino acid sequence of SEQID NO: 219, the HCDR2 comprises the amino acid sequence of SEQ ID NO:220, the HCDR3 comprises the amino acid sequence of SEQ ID NO: 221, theLCDR1 comprises the amino acid sequence of SEQ ID NO: 235, the LCDR2comprises the amino acid sequence of SEQ ID NO: 236, and the LCDR3comprises the amino acid sequence of SEQ ID NO: 237; ii) the HCDR1comprises the amino acid sequence of SEQ ID NO: 222, the HCDR2 comprisesthe amino acid sequence of SEQ ID NO: 223, the HCDR3 comprises the aminoacid sequence of SEQ ID NO: 224, the LCDR1 comprises the amino acidsequence of SEQ ID NO: 238, the LCDR2 comprises the amino acid sequenceof SEQ ID NO: 239, and the LCDR3 comprises the amino acid sequence ofSEQ ID NO: 240; iii) the HCDR1 comprises the amino acid sequence of SEQID NO: 225, the HCDR2 comprises the amino acid sequence of SEQ ID NO:226, the HCDR3 comprises the amino acid sequence of SEQ ID NO: 227, theLCDR1 comprises the amino acid sequence of SEQ ID NO: 241, the LCDR2comprises the amino acid sequence of SEQ ID NO: 242, and the LCDR3comprises the amino acid sequence of SEQ ID NO: 243; or iv) the HCDR1comprises the amino acid sequence of SEQ ID NO: 228, the HCDR2 comprisesthe amino acid sequence of SEQ ID NO: 229, the HCDR3 comprises the aminoacid sequence of SEQ ID NO: 230, the LCDR1 comprises the amino acidsequence of SEQ ID NO: 244, the LCDR2 comprises the amino acid sequenceof SEQ ID NO: 245, and the LCDR3 comprises the amino acid sequence ofSEQ ID NO: 246; h) i) the HCDR1 comprises the amino acid sequence of SEQID NO: 251, the HCDR2 comprises the amino acid sequence of SEQ ID NO:252, the HCDR3 comprises the amino acid sequence of SEQ ID NO: 253, theLCDR1 comprises the amino acid sequence of SEQ ID NO: 267, the LCDR2comprises the amino acid sequence of SEQ ID NO: 268, and the LCDR3comprises the amino acid sequence of SEQ ID NO: 269; ii) the HCDR1comprises the amino acid sequence of SEQ ID NO: 254, the HCDR2 comprisesthe amino acid sequence of SEQ ID NO: 255, the HCDR3 comprises the aminoacid sequence of SEQ ID NO: 256, the LCDR1 comprises the amino acidsequence of SEQ ID NO: 270, the LCDR2 comprises the amino acid sequenceof SEQ ID NO: 271, and the LCDR3 comprises the amino acid sequence ofSEQ ID NO: 272; iii) the HCDR1 comprises the amino acid sequence of SEQID NO: 257, the HCDR2 comprises the amino acid sequence of SEQ ID NO:258, the HCDR3 comprises the amino acid sequence of SEQ ID NO: 259, theLCDR1 comprises the amino acid sequence of SEQ ID NO: 273, the LCDR2comprises the amino acid sequence of SEQ ID NO: 274, and the LCDR3comprises the amino acid sequence of SEQ ID NO: 275; or iv) the HCDR1comprises the amino acid sequence of SEQ ID NO: 260, the HCDR2 comprisesthe amino acid sequence of SEQ ID NO: 261, the HCDR3 comprises the aminoacid sequence of SEQ ID NO: 262, the LCDR1 comprises the amino acidsequence of SEQ ID NO: 276, the LCDR2 comprises the amino acid sequenceof SEQ ID NO: 277, and the LCDR3 comprises the amino acid sequence ofSEQ ID NO: 278; i) i) the HCDR1 comprises the amino acid sequence of SEQID NO: 283, the HCDR2 comprises the amino acid sequence of SEQ ID NO:284, the HCDR3 comprises the amino acid sequence of SEQ ID NO: 285, theLCDR1 comprises the amino acid sequence of SEQ ID NO: 299, the LCDR2comprises the amino acid sequence of SEQ ID NO: 300, and the LCDR3comprises the amino acid sequence of SEQ ID NO: 301; ii) the HCDR1comprises the amino acid sequence of SEQ ID NO: 286, the HCDR2 comprisesthe amino acid sequence of SEQ ID NO: 287, the HCDR3 comprises the aminoacid sequence of SEQ ID NO: 288, the LCDR1 comprises the amino acidsequence of SEQ ID NO: 302, the LCDR2 comprises the amino acid sequenceof SEQ ID NO: 303, and the LCDR3 comprises the amino acid sequence ofSEQ ID NO: 304; iii) the HCDR1 comprises the amino acid sequence of SEQID NO: 289, the HCDR2 comprises the amino acid sequence of SEQ ID NO:290, the HCDR3 comprises the amino acid sequence of SEQ ID NO: 291, theLCDR1 comprises the amino acid sequence of SEQ ID NO: 305, the LCDR2comprises the amino acid sequence of SEQ ID NO: 306, and the LCDR3comprises the amino acid sequence of SEQ ID NO: 307; or iv) the HCDR1comprises the amino acid sequence of SEQ ID NO: 292, the HCDR2 comprisesthe amino acid sequence of SEQ ID NO: 293, the HCDR3 comprises the aminoacid sequence of SEQ ID NO: 294, the LCDR1 comprises the amino acidsequence of SEQ ID NO: 308, the LCDR2 comprises the amino acid sequenceof SEQ ID NO: 309, and the LCDR3 comprises the amino acid sequence ofSEQ ID NO: 310; or j) i) the HCDR1 comprises the amino acid sequence ofSEQ ID NO: 315, the HCDR2 comprises the amino acid sequence of SEQ IDNO: 316, the HCDR3 comprises the amino acid sequence of SEQ ID NO: 317,the LCDR1 comprises the amino acid sequence of SEQ ID NO: 331, the LCDR2comprises the amino acid sequence of SEQ ID NO: 332, and the LCDR3comprises the amino acid sequence of SEQ ID NO: 333; ii) the HCDR1comprises the amino acid sequence of SEQ ID NO: 318, the HCDR2 comprisesthe amino acid sequence of SEQ ID NO: 319, the HCDR3 comprises the aminoacid sequence of SEQ ID NO: 320, the LCDR1 comprises the amino acidsequence of SEQ ID NO: 334, the LCDR2 comprises the amino acid sequenceof SEQ ID NO: 335, and the LCDR3 comprises the amino acid sequence ofSEQ ID NO: 336; iii) the HCDR1 comprises the amino acid sequence of SEQID NO: 321, the HCDR2 comprises the amino acid sequence of SEQ ID NO:322, the HCDR3 comprises the amino acid sequence of SEQ ID NO: 323, theLCDR1 comprises the amino acid sequence of SEQ ID NO: 337, the LCDR2comprises the amino acid sequence of SEQ ID NO: 338, and the LCDR3comprises the amino acid sequence of SEQ ID NO: 339; or iv) the HCDR1comprises the amino acid sequence of SEQ ID NO: 324, the HCDR2 comprisesthe amino acid sequence of SEQ ID NO: 325, the HCDR3 comprises the aminoacid sequence of SEQ ID NO: 326, the LCDR1 comprises the amino acidsequence of SEQ ID NO: 340, the LCDR2 comprises the amino acid sequenceof SEQ ID NO: 341, and the LCDR3 comprises the amino acid sequence ofSEQ ID NO:
 342. 32. A vector comprising the polynucleotide of claim 31.33. A host cell comprising the polynucleotide of claim
 31. 34. A hostcell comprising the vector of claim
 32. 35. A method of producing abinding agent, wherein said method comprises culturing the host cell ofclaim 33 under suitable conditions for expression of the binding agentor a portion thereof, wherein the method optionally comprises purifyingthe binding agent. 36-71. (canceled)
 72. The polynucleotide of claim 31,wherein the binding agent comprises: a) a VH comprising the amino acidsequence of SEQ ID NO: 103 and a VL comprising the amino acid sequenceof SEQ ID NO: 119; b) a VH comprising the amino acid sequence of SEQ IDNO: 39 and a VL comprising the amino acid sequence of SEQ ID NO: 55; c)a VH comprising the amino acid sequence of SEQ ID NO: 71 and a VLcomprising the amino acid sequence of SEQ ID NO: 87; d) a VH comprisingthe amino acid sequence of SEQ ID NO: 135 and a VL comprising the aminoacid sequence of SEQ ID NO: 151; e) a VH comprising the amino acidsequence of SEQ ID NO: 167 and a VL comprising the amino acid sequenceof SEQ ID NO: 183; f) a VH comprising the amino acid sequence of SEQ IDNO: 199 and a VL comprising the amino acid sequence of SEQ ID NO: 215;g) a VH comprising the amino acid sequence of SEQ ID NO: 231 and a VLcomprising the amino acid sequence of SEQ ID NO: 247; h) a VH comprisingthe amino acid sequence of SEQ ID NO: 263 and a VL comprising the aminoacid sequence of SEQ ID NO: 279; i) a VH comprising the amino acidsequence of SEQ ID NO: 295 and a VL comprising the amino acid sequenceof SEQ ID NO: 311; or j) a VH comprising the amino acid sequence of SEQID NO: 327 and a VL comprising the amino acid sequence of SEQ ID NO:343.
 73. The polynucleotide of claim 31, wherein the binding agentcomprises: a) a VH comprising an amino acid sequence that is at least90% identical to the amino acid sequence of SEQ ID NO: 103 and a VLcomprising an amino acid sequence that is at least 90% identical to theamino acid sequence of SEQ ID NO: 119; b) a VH comprising an amino acidsequence that is at least 90% identical to the amino acid sequence ofSEQ ID NO: 39 and a VL comprising an amino acid sequence that is atleast 90% identical to the amino acid sequence of SEQ ID NO: 55; c) a VHcomprising an amino acid sequence that is at least 90% identical to theamino acid sequence of SEQ ID NO: 71 and a VL comprising an amino acidsequence that is at least 90% identical to the amino acid sequence ofSEQ ID NO: 87; d) a VH comprising an amino acid sequence that is atleast 90% identical to the amino acid sequence of SEQ ID NO: 135 and aVL comprising an amino acid sequence that is at least 90% identical tothe amino acid sequence of SEQ ID NO: 151; e) a VH comprising an aminoacid sequence that is at least 90% identical to the amino acid sequenceof SEQ ID NO: 167 and a VL comprising an amino acid sequence that is atleast 90% identical to the amino acid sequence of SEQ ID NO: 183; f) aVH comprising an amino acid sequence that is at least 90% identical tothe amino acid sequence of SEQ ID NO: 199 and a VL comprising an aminoacid sequence that is at least 90% identical to the amino acid sequenceof SEQ ID NO: 215; g) a VH comprising an amino acid sequence that is atleast 90% identical to the amino acid sequence of SEQ ID NO: 231 and aVL comprising an amino acid sequence that is at least 90% identical tothe amino acid sequence of SEQ ID NO: 247; h) a VH comprising amino acidsequence that is at least 90% identical to the amino acid sequence ofSEQ ID NO: 263 and a VL comprising an amino acid sequence that is atleast 90% identical to the amino acid sequence of SEQ ID NO: 279; i) aVH comprising an amino acid sequence that is at least 90% identical tothe amino acid sequence of SEQ ID NO: 295 and a VL comprising an aminoacid sequence that is at least 90% identical to the amino acid sequenceof SEQ ID NO: 311; or j) a VH comprising an amino acid sequence that isat least 90% identical to the amino acid sequence of SEQ ID NO: 327 anda VL comprising an amino acid sequence that is at least 90% identical tothe amino acid sequence of SEQ ID NO:
 343. 74. The polynucleotide ofclaim 31, wherein the binding agent is an antibody comprising a heavychain and a light chain, and wherein: a) the heavy chain comprises theamino acid sequence of SEQ ID NO: 105 and the light chain comprises theamino acid sequence of SEQ ID NO: 121; b) the heavy chain comprises theamino acid sequence of SEQ ID NO: 41 and the light chain comprises theamino acid sequence of SEQ ID NO: 57; c) the heavy chain comprises theamino acid sequence of SEQ ID NO: 73 and the light chain comprises theamino acid sequence of SEQ ID NO: 89; d) the heavy chain comprises theamino acid sequence of SEQ ID NO: 137 and the light chain comprises theamino acid sequence of SEQ ID NO: 153; e) the heavy chain comprises theamino acid sequence of SEQ ID NO: 169 and the light chain comprises theamino acid sequence of SEQ ID NO: 185; f) the heavy chain comprises theamino acid sequence of SEQ ID NO: 201 and the light chain comprises theamino acid sequence of SEQ ID NO: 217; g) the heavy chain comprises theamino acid sequence of SEQ ID NO: 233 and the light chain comprises theamino acid sequence of SEQ ID NO: 249; h) the heavy chain comprises theamino acid sequence of SEQ ID NO: 265 and the light chain comprises theamino acid sequence of SEQ ID NO: 281; i) the heavy chain comprises theamino acid sequence of SEQ ID NO: 297 and the light chain comprises theamino acid sequence of SEQ ID NO: 313; or j) the heavy chain comprisesthe amino acid sequence of SEQ ID NO: 329 and the light chain comprisesthe amino acid sequence of SEQ ID NO:
 345. 75. The polynucleotide ofclaim 31, wherein the binding agent is an antibody Fab fragment.
 76. Thepolynucleotide of claim 31, wherein the binding agent is a monoclonalhuman antibody.
 77. A method of producing a binding agent, wherein saidmethod comprises culturing the host cell of claim 34 under suitableconditions for expression of the binding agent or a portion thereof,wherein the method optionally comprises purifying the binding agent. 78.A pharmaceutical composition comprising the binding agent produced bythe method of claim 35 and a pharmaceutically acceptable carrier.
 79. Apharmaceutical composition comprising the binding agent produced by themethod of claim 77 and a pharmaceutically acceptable carrier.
 80. Amethod for reversing the anticoagulant effect of an anti-FXI/FXIaantibody or antigen-binding fragment thereof in a patient being treatedwith said anti-FXI/FXIa antibody or antigen-binding fragment thereof,wherein the method comprises administering an effective amount of abinding agent which specifically binds the anti-FXI/FXIa antibody,wherein the anti-FXI/FXIa antibody or antigen-binding fragment thereofcomprises a heavy chain variable region (VH) comprising complementaritydetermining regions HCDR1, HCDR2 and HCDR3 of a VH comprising the aminoacid sequence of SEQ ID NO: 12 and a light chain variable region (VL)comprising complementarity determining regions LCDR1, LCDR2, and LCDR3of a VL comprising the amino acid sequence of SEQ ID NO: 23, and whereinthe binding agent is an antibody or antigen-binding fragment thereofwherein: a) i) the HCDR1 comprises the amino acid sequence of SEQ ID NO:27, the HCDR2 comprises the amino acid sequence of SEQ ID NO: 28, theHCDR3 comprises the amino acid sequence of SEQ ID NO: 29, the LCDR1comprises the amino acid sequence of SEQ ID NO: 43, the LCDR2 comprisesthe amino acid sequence of SEQ ID NO: 44, and the LCDR3 comprises theamino acid sequence of SEQ ID NO: 45; ii) the HCDR1 comprises the aminoacid sequence of SEQ ID NO: 30, the HCDR2 comprises the amino acidsequence of SEQ ID NO: 31, the HCDR3 comprises the amino acid sequenceof SEQ ID NO: 32, the LCDR1 comprises the amino acid sequence of SEQ IDNO: 46, the LCDR2 comprises the amino acid sequence of SEQ ID NO: 47,and the LCDR3 comprises the amino acid sequence of SEQ ID NO: 48; iii)the HCDR1 comprises the amino acid sequence of SEQ ID NO: 33, the HCDR2comprises the amino acid sequence of SEQ ID NO: 34, the HCDR3 comprisesthe amino acid sequence of SEQ ID NO: 35, the LCDR1 comprises the aminoacid sequence of SEQ ID NO: 49, the LCDR2 comprises the amino acidsequence of SEQ ID NO: 50, and the LCDR3 comprises the amino acidsequence of SEQ ID NO: 51; or iv) the HCDR1 comprises the amino acidsequence of SEQ ID NO: 36, the HCDR2 comprises the amino acid sequenceof SEQ ID NO: 37, the HCDR3 comprises the amino acid sequence of SEQ IDNO: 38, the LCDR1 comprises the amino acid sequence of SEQ ID NO: 52,the LCDR2 comprises the amino acid sequence of SEQ ID NO: 53, and theLCDR3 comprises the amino acid sequence of SEQ ID NO: 54; b) i) theHCDR1 comprises the amino acid sequence of SEQ ID NO: 59, the HCDR2comprises the amino acid sequence of SEQ ID NO: 60, the HCDR3 comprisesthe amino acid sequence of SEQ ID NO: 61, the LCDR1 comprises the aminoacid sequence of SEQ ID NO: 75, the LCDR2 comprises the amino acidsequence of SEQ ID NO: 76, and the LCDR3 comprises the amino acidsequence of SEQ ID NO: 77; ii) the HCDR1 comprises the amino acidsequence of SEQ ID NO: 62, the HCDR2 comprises the amino acid sequenceof SEQ ID NO: 63, the HCDR3 comprises the amino acid sequence of SEQ IDNO: 64, the LCDR1 comprises the amino acid sequence of SEQ ID NO: 78,the LCDR2 comprises the amino acid sequence of SEQ ID NO: 79, and theLCDR3 comprises the amino acid sequence of SEQ ID NO: 80; iii) the HCDR1comprises the amino acid sequence of SEQ ID NO: 65, the HCDR2 comprisesthe amino acid sequence of SEQ ID NO: 66, the HCDR3 comprises the aminoacid sequence of SEQ ID NO: 67, the LCDR1 comprises the amino acidsequence of SEQ ID NO: 81, the LCDR2 comprises the amino acid sequenceof SEQ ID NO: 82, and the LCDR3 comprises the amino acid sequence of SEQID NO: 83; or iv) the HCDR1 comprises the amino acid sequence of SEQ IDNO: 68, the HCDR2 comprises the amino acid sequence of SEQ ID NO: 69,the HCDR3 comprises the amino acid sequence of SEQ ID NO: 70, the LCDR1comprises the amino acid sequence of SEQ ID NO: 84, the LCDR2 comprisesthe amino acid sequence of SEQ ID NO: 85, and the LCDR3 comprises theamino acid sequence of SEQ ID NO: 86; c) i) the HCDR1 comprises theamino acid sequence of SEQ ID NO: 123, the HCDR2 comprises the aminoacid sequence of SEQ ID NO: 124, the HCDR3 comprises the amino acidsequence of SEQ ID NO: 125, the LCDR1 comprises the amino acid sequenceof SEQ ID NO: 139, the LCDR2 comprises the amino acid sequence of SEQ IDNO: 140, and the LCDR3 comprises the amino acid sequence of SEQ ID NO:141; ii) the HCDR1 comprises the amino acid sequence of SEQ ID NO: 126,the HCDR2 comprises the amino acid sequence of SEQ ID NO: 127, the HCDR3comprises the amino acid sequence of SEQ ID NO: 128, the LCDR1 comprisesthe amino acid sequence of SEQ ID NO: 142, the LCDR2 comprises the aminoacid sequence of SEQ ID NO: 143, and the LCDR3 comprises the amino acidsequence of SEQ ID NO: 144; iii) the HCDR1 comprises the amino acidsequence of SEQ ID NO: 129, the HCDR2 comprises the amino acid sequenceof SEQ ID NO: 130, the HCDR3 comprises the amino acid sequence of SEQ IDNO: 131, the LCDR1 comprises the amino acid sequence of SEQ ID NO: 145,the LCDR2 comprises the amino acid sequence of SEQ ID NO: 146, and theLCDR3 comprises the amino acid sequence of SEQ ID NO: 147; or iv) theHCDR1 comprises the amino acid sequence of SEQ ID NO: 132, the HCDR2comprises the amino acid sequence of SEQ ID NO: 133, the HCDR3 comprisesthe amino acid sequence of SEQ ID NO: 134, the LCDR1 comprises the aminoacid sequence of SEQ ID NO: 148, the LCDR2 comprises the amino acidsequence of SEQ ID NO: 149, and the LCDR3 comprises the amino acidsequence of SEQ ID NO: 150; d) i) the HCDR1 comprises the amino acidsequence of SEQ ID NO: 155, the HCDR2 comprises the amino acid sequenceof SEQ ID NO: 156, the HCDR3 comprises the amino acid sequence of SEQ IDNO: 157, the LCDR1 comprises the amino acid sequence of SEQ ID NO: 171,the LCDR2 comprises the amino acid sequence of SEQ ID NO: 172, and theLCDR3 comprises the amino acid sequence of SEQ ID NO: 173; ii) the HCDR1comprises the amino acid sequence of SEQ ID NO: 158, the HCDR2 comprisesthe amino acid sequence of SEQ ID NO: 159, the HCDR3 comprises the aminoacid sequence of SEQ ID NO: 160, the LCDR1 comprises the amino acidsequence of SEQ ID NO: 174, the LCDR2 comprises the amino acid sequenceof SEQ ID NO: 175, and the LCDR3 comprises the amino acid sequence ofSEQ ID NO: 176; iii) the HCDR1 comprises the amino acid sequence of SEQID NO: 161, the HCDR2 comprises the amino acid sequence of SEQ ID NO:162, the HCDR3 comprises the amino acid sequence of SEQ ID NO: 163, theLCDR1 comprises the amino acid sequence of SEQ ID NO: 177, the LCDR2comprises the amino acid sequence of SEQ ID NO: 178, and the LCDR3comprises the amino acid sequence of SEQ ID NO: 179; or iv) the HCDR1comprises the amino acid sequence of SEQ ID NO: 164, the HCDR2 comprisesthe amino acid sequence of SEQ ID NO: 165, the HCDR3 comprises the aminoacid sequence of SEQ ID NO: 166, the LCDR1 comprises the amino acidsequence of SEQ ID NO: 180, the LCDR2 comprises the amino acid sequenceof SEQ ID NO: 181, and the LCDR3 comprises the amino acid sequence ofSEQ ID NO: 182; e) i) the HCDR1 comprises the amino acid sequence of SEQID NO: 187, the HCDR2 comprises the amino acid sequence of SEQ ID NO:188, the HCDR3 comprises the amino acid sequence of SEQ ID NO: 189, theLCDR1 comprises the amino acid sequence of SEQ ID NO: 203, the LCDR2comprises the amino acid sequence of SEQ ID NO: 204, and the LCDR3comprises the amino acid sequence of SEQ ID NO: 205; ii) the HCDR1comprises the amino acid sequence of SEQ ID NO: 190, the HCDR2 comprisesthe amino acid sequence of SEQ ID NO: 191, the HCDR3 comprises the aminoacid sequence of SEQ ID NO: 192, the LCDR1 comprises the amino acidsequence of SEQ ID NO: 206, the LCDR2 comprises the amino acid sequenceof SEQ ID NO: 207, and the LCDR3 comprises the amino acid sequence ofSEQ ID NO: 208; iii) the HCDR1 comprises the amino acid sequence of SEQID NO: 193, the HCDR2 comprises the amino acid sequence of SEQ ID NO:194, the HCDR3 comprises the amino acid sequence of SEQ ID NO: 195, theLCDR1 comprises the amino acid sequence of SEQ ID NO: 209, the LCDR2comprises the amino acid sequence of SEQ ID NO: 210, and the LCDR3comprises the amino acid sequence of SEQ ID NO: 211; or iv) the HCDR1comprises the amino acid sequence of SEQ ID NO: 196, the HCDR2 comprisesthe amino acid sequence of SEQ ID NO: 197, the HCDR3 comprises the aminoacid sequence of SEQ ID NO: 198, the LCDR1 comprises the amino acidsequence of SEQ ID NO: 212, the LCDR2 comprises the amino acid sequenceof SEQ ID NO: 213, and the LCDR3 comprises the amino acid sequence ofSEQ ID NO: 214; f) i) the HCDR1 comprises the amino acid sequence of SEQID NO: 219, the HCDR2 comprises the amino acid sequence of SEQ ID NO:220, the HCDR3 comprises the amino acid sequence of SEQ ID NO: 221, theLCDR1 comprises the amino acid sequence of SEQ ID NO: 235, the LCDR2comprises the amino acid sequence of SEQ ID NO: 236, and the LCDR3comprises the amino acid sequence of SEQ ID NO: 237; ii) the HCDR1comprises the amino acid sequence of SEQ ID NO: 222, the HCDR2 comprisesthe amino acid sequence of SEQ ID NO: 223, the HCDR3 comprises the aminoacid sequence of SEQ ID NO: 224, the LCDR1 comprises the amino acidsequence of SEQ ID NO: 238, the LCDR2 comprises the amino acid sequenceof SEQ ID NO: 239, and the LCDR3 comprises the amino acid sequence ofSEQ ID NO: 240; iii) the HCDR1 comprises the amino acid sequence of SEQID NO: 225, the HCDR2 comprises the amino acid sequence of SEQ ID NO:226, the HCDR3 comprises the amino acid sequence of SEQ ID NO: 227, theLCDR1 comprises the amino acid sequence of SEQ ID NO: 241, the LCDR2comprises the amino acid sequence of SEQ ID NO: 242, and the LCDR3comprises the amino acid sequence of SEQ ID NO: 243; or iv) the HCDR1comprises the amino acid sequence of SEQ ID NO: 228, the HCDR2 comprisesthe amino acid sequence of SEQ ID NO: 229, the HCDR3 comprises the aminoacid sequence of SEQ ID NO: 230, the LCDR1 comprises the amino acidsequence of SEQ ID NO: 244, the LCDR2 comprises the amino acid sequenceof SEQ ID NO: 245, and the LCDR3 comprises the amino acid sequence ofSEQ ID NO: 246; g) i) the HCDR1 comprises the amino acid sequence of SEQID NO: 251, the HCDR2 comprises the amino acid sequence of SEQ ID NO:252, the HCDR3 comprises the amino acid sequence of SEQ ID NO: 253, theLCDR1 comprises the amino acid sequence of SEQ ID NO: 267, the LCDR2comprises the amino acid sequence of SEQ ID NO: 268, and the LCDR3comprises the amino acid sequence of SEQ ID NO: 269; ii) the HCDR1comprises the amino acid sequence of SEQ ID NO: 254, the HCDR2 comprisesthe amino acid sequence of SEQ ID NO: 255, the HCDR3 comprises the aminoacid sequence of SEQ ID NO: 256, the LCDR1 comprises the amino acidsequence of SEQ ID NO: 270, the LCDR2 comprises the amino acid sequenceof SEQ ID NO: 271, and the LCDR3 comprises the amino acid sequence ofSEQ ID NO: 272; iii) the HCDR1 comprises the amino acid sequence of SEQID NO: 257, the HCDR2 comprises the amino acid sequence of SEQ ID NO:258, the HCDR3 comprises the amino acid sequence of SEQ ID NO: 259, theLCDR1 comprises the amino acid sequence of SEQ ID NO: 273, the LCDR2comprises the amino acid sequence of SEQ ID NO: 274, and the LCDR3comprises the amino acid sequence of SEQ ID NO: 275; or iv) the HCDR1comprises the amino acid sequence of SEQ ID NO: 260, the HCDR2 comprisesthe amino acid sequence of SEQ ID NO: 261, the HCDR3 comprises the aminoacid sequence of SEQ ID NO: 262, the LCDR1 comprises the amino acidsequence of SEQ ID NO: 276, the LCDR2 comprises the amino acid sequenceof SEQ ID NO: 277, and the LCDR3 comprises the amino acid sequence ofSEQ ID NO: 278; h) i) the HCDR1 comprises the amino acid sequence of SEQID NO: 283, the HCDR2 comprises the amino acid sequence of SEQ ID NO:284, the HCDR3 comprises the amino acid sequence of SEQ ID NO: 285, theLCDR1 comprises the amino acid sequence of SEQ ID NO: 299, the LCDR2comprises the amino acid sequence of SEQ ID NO: 300, and the LCDR3comprises the amino acid sequence of SEQ ID NO: 301; ii) the HCDR1comprises the amino acid sequence of SEQ ID NO: 286, the HCDR2 comprisesthe amino acid sequence of SEQ ID NO: 287, the HCDR3 comprises the aminoacid sequence of SEQ ID NO: 288, the LCDR1 comprises the amino acidsequence of SEQ ID NO: 302, the LCDR2 comprises the amino acid sequenceof SEQ ID NO: 303, and the LCDR3 comprises the amino acid sequence ofSEQ ID NO: 304; iii) the HCDR1 comprises the amino acid sequence of SEQID NO: 289, the HCDR2 comprises the amino acid sequence of SEQ ID NO:290, the HCDR3 comprises the amino acid sequence of SEQ ID NO: 291, theLCDR1 comprises the amino acid sequence of SEQ ID NO: 305, the LCDR2comprises the amino acid sequence of SEQ ID NO: 306, and the LCDR3comprises the amino acid sequence of SEQ ID NO: 307; or iv) the HCDR1comprises the amino acid sequence of SEQ ID NO: 292, the HCDR2 comprisesthe amino acid sequence of SEQ ID NO: 293, the HCDR3 comprises the aminoacid sequence of SEQ ID NO: 294, the LCDR1 comprises the amino acidsequence of SEQ ID NO: 308, the LCDR2 comprises the amino acid sequenceof SEQ ID NO: 309, and the LCDR3 comprises the amino acid sequence ofSEQ ID NO: 310; or i) i) the HCDR1 comprises the amino acid sequence ofSEQ ID NO: 315, the HCDR2 comprises the amino acid sequence of SEQ IDNO: 316, the HCDR3 comprises the amino acid sequence of SEQ ID NO: 317,the LCDR1 comprises the amino acid sequence of SEQ ID NO: 331, the LCDR2comprises the amino acid sequence of SEQ ID NO: 332, and the LCDR3comprises the amino acid sequence of SEQ ID NO: 333; ii) the HCDR1comprises the amino acid sequence of SEQ ID NO: 318, the HCDR2 comprisesthe amino acid sequence of SEQ ID NO: 319, the HCDR3 comprises the aminoacid sequence of SEQ ID NO: 320, the LCDR1 comprises the amino acidsequence of SEQ ID NO: 334, the LCDR2 comprises the amino acid sequenceof SEQ ID NO: 335, and the LCDR3 comprises the amino acid sequence ofSEQ ID NO: 336; iii) the HCDR1 comprises the amino acid sequence of SEQID NO: 321, the HCDR2 comprises the amino acid sequence of SEQ ID NO:322, the HCDR3 comprises the amino acid sequence of SEQ ID NO: 323, theLCDR1 comprises the amino acid sequence of SEQ ID NO: 337, the LCDR2comprises the amino acid sequence of SEQ ID NO: 338, and the LCDR3comprises the amino acid sequence of SEQ ID NO: 339; or iv) the HCDR1comprises the amino acid sequence of SEQ ID NO: 324, the HCDR2 comprisesthe amino acid sequence of SEQ ID NO: 325, the HCDR3 comprises the aminoacid sequence of SEQ ID NO: 326, the LCDR1 comprises the amino acidsequence of SEQ ID NO: 340, the LCDR2 comprises the amino acid sequenceof SEQ ID NO: 341, and the LCDR3 comprises the amino acid sequence ofSEQ ID NO: 342; and wherein the binding agent is isolated from a hostcell comprising a polynucleotide encoding said binding agent.
 81. Themethod of claim 80, wherein the anti-FXI/FXIa antibody orantigen-binding fragment thereof comprises: a) a VH comprisingcomplementarity determining regions HCDR1, HCDR2, and HCDR3 comprisingthe amino acid sequences of SEQ ID NO: 6, SEQ ID NO: 4, and SEQ ID NO:5, respectively; and a VL comprising complementarity determining regionsLCDR1, LCDR2, and LCDR3 comprising the amino acid sequence of SEQ ID NO:16, SEQ ID NO: 17, and SEQ ID NO: 18, respectively; b) a VH comprisingcomplementarity determining regions HCDR1, HCDR2, and HCDR3 comprisingthe amino acid sequences of SEQ ID NO: 7, SEQ ID NO: 8, and SEQ ID NO:5, respectively; and a VL comprising complementarity determining regionsLCDR1, LCDR2, and LCDR3 comprising the amino acid sequence of SEQ ID NO:19, SEQ ID NO: 20, and SEQ ID NO: 21, respectively; c) a VH comprisingcomplementarity determining regions HCDR1, HCDR2, and HCDR3 comprisingthe amino acid sequences of SEQ ID NO: 9, SEQ ID NO: 10, and SEQ ID NO:11, respectively; and (ii) a VL comprising complementarity determiningregions LCDR1, LCDR2, and LCDR3 comprising the amino acid sequence ofSEQ ID NO: 22, SEQ ID NO: 20, and SEQ ID NO: 18, respectively; or d) aVH comprising complementarity determining regions HCDR1, HCDR2, andHCDR3 comprising the amino acid sequences of SEQ ID NO: 3, SEQ ID NO: 4,and SEQ ID NO: 5, respectively; and (ii) a VL comprising complementaritydetermining regions LCDR1, LCDR2, and LCDR3 comprising the amino acidsequence of SEQ ID NO: 16, SEQ ID NO: 17, and SEQ ID NO: 18,respectively.
 82. The method of claim 80, wherein the anti-FXI/FXIaantibody or antigen-binding fragment thereof comprises a VH comprisingthe amino acid sequence of SEQ ID NO: 12 and a VL comprising the aminoacid sequence of SEQ ID NO:
 23. 83. The method of claim 80, wherein theanti-FXI/FXIa antibody comprises a heavy chain comprising the amino acidsequence of SEQ ID NO: 14 and a light chain comprising the amino acidsequence of SEQ ID NO:
 25. 84. The method of claim 80, wherein thebinding agent comprises: a) a VH comprising the amino acid sequence ofSEQ ID NO: 39 and a VL comprising the amino acid sequence of SEQ ID NO:55; b) a VH comprising the amino acid sequence of SEQ ID NO: 71 and a VLcomprising the amino acid sequence of SEQ ID NO: 87; c) a VH comprisingthe amino acid sequence of SEQ ID NO: 135 and a VL comprising the aminoacid sequence of SEQ ID NO: 151; d) a VH comprising the amino acidsequence of SEQ ID NO: 167 and a VL comprising the amino acid sequenceof SEQ ID NO: 183; e) a VH comprising the amino acid sequence of SEQ IDNO: 199 and a VL comprising the amino acid sequence of SEQ ID NO: 215;f) a VH comprising the amino acid sequence of SEQ ID NO: 231 and a VLcomprising the amino acid sequence of SEQ ID NO: 247; g) a VH comprisingthe amino acid sequence of SEQ ID NO: 263 and a VL comprising the aminoacid sequence of SEQ ID NO: 279; h) a VH comprising the amino acidsequence of SEQ ID NO: 295 and a VL comprising the amino acid sequenceof SEQ ID NO: 311; or i) a VH comprising the amino acid sequence of SEQID NO: 327 and a VL comprising the amino acid sequence of SEQ ID NO:343.
 85. The method of claim 80, wherein the binding agent is anantibody comprising a heavy chain and a light chain, and wherein: a) theheavy chain comprises the amino acid sequence of SEQ ID NO: 41 and thelight chain comprises the amino acid sequence of SEQ ID NO: 57; b) theheavy chain comprises the amino acid sequence of SEQ ID NO: 73 and thelight chain comprises the amino acid sequence of SEQ ID NO: 89; c) theheavy chain comprises the amino acid sequence of SEQ ID NO: 137 and thelight chain comprises the amino acid sequence of SEQ ID NO: 153; d) theheavy chain comprises the amino acid sequence of SEQ ID NO: 169 and thelight chain comprises the amino acid sequence of SEQ ID NO: 185; e) theheavy chain comprises the amino acid sequence of SEQ ID NO: 201 and thelight chain comprises the amino acid sequence of SEQ ID NO: 217; f) theheavy chain comprises the amino acid sequence of SEQ ID NO: 233 and thelight chain comprises the amino acid sequence of SEQ ID NO: 249; g) theheavy chain comprises the amino acid sequence of SEQ ID NO: 265 and thelight chain comprises the amino acid sequence of SEQ ID NO: 281; h) theheavy chain comprises the amino acid sequence of SEQ ID NO: 297 and thelight chain comprises the amino acid sequence of SEQ ID NO: 313; or i)the heavy chain comprises the amino acid sequence of SEQ ID NO: 329 andthe light chain comprises the amino acid sequence of SEQ ID NO:
 345. 86.The method of claim 80, wherein the method further comprises applyingone or more of the following to the patient: (i) fluid replacement usingcolloids, crystalloids, human plasma or plasma proteins such as albumin;(ii) transfusion with packed red blood or whole blood; and (iii)administration of fresh frozen plasma (FFP), prothrombin complexconcentrates (PCC), activated PCC (APCC) such as factor VIII inhibitor,and/or recombinant, activated factor VII.